Identification of clear cell renal cell carcinoma subtypes by integrating radiomics and transcriptomics.

Objective: This study aimed to delineate the clear cell renal cell carcinoma (ccRCC) intrinsic subtypes through unsupervised clustering of radiomics and transcriptomics data and to evaluate their associations with clinicopathological features, prognosis, and molecular characteristics. Methods: Using a retrospective dual-center approach, we gathered transcriptomic and clinical data from ccRCC patients registered in The Cancer Genome Atlas and contrast-enhanced computed tomography images from The Cancer Imaging Archive and local databases. Following the segmentation of images, radiomics feature extraction, and feature preprocessing, we performed unsupervised clustering based on the "CancerSubtypes" package to identify distinct radiotranscriptomic subtypes, which were then correlated with clinical-pathological, prognostic, immune, and molecular characteristics. Results: Clustering identified three subtypes, C1, C2, and C3, each of which displayed unique clinicopathological, prognostic, immune, and molecular distinctions. Notably, subtypes C1 and C3 were associated with poorer survival outcomes than subtype C2. Pathway analysis highlighted immune pathway activation in C1 and metabolic pathway prominence in C2. Gene mutation analysis identified VHL and PBRM1 as the most commonly mutated genes, with more mutated genes observed in the C3 subtype. Despite similar tumor mutation burdens, microsatellite instability, and RNA interference across subtypes, C1 and C3 demonstrated greater tumor immune dysfunction and rejection. In the validation cohort, the various subtypes showed comparable results in terms of clinicopathological features and prognosis to those observed in the training cohort, thus confirming the efficacy of our algorithm. Conclusion: Unsupervised clustering based on radiotranscriptomics can identify the intrinsic subtypes of ccRCC, and radiotranscriptomic subtypes can characterize the prognosis and molecular features of tumors, enabling noninvasive tumor risk stratification.

Prediction of blood-brain barrier permeability using machine learning approaches based on various molecular representation.

The assessment of compound blood-brain barrier (BBB) permeability poses a significant challenge in the discovery of drugs targeting the central nervous system. Conventional experimental approaches to measure BBB permeability are labor-intensive, cost-ineffective, and time-consuming. In this study, we constructed six machine learning classification models by combining various machine learning algorithms and molecular representations. The model based on ExtraTree algorithm and random partitioning strategy obtains the best prediction result, with AUC value of 0.932±0.004 and balanced accuracy (BA) of 0.837±0.010 for the test set. We employed the SHAP method to identify important features associated with BBB permeability. In addition, matched molecular pair (MMP) analysis and representative substructure derivation method were utilized to uncover the transformation rules and distinctive structural features of BBB permeable compounds. The machine learning models proposed in this work can serve as an effective tool for assessing BBB permeability in the drug discovery for central nervous system disease.

The mechanism of resveratrol stabilization and degradation by synergistic interactions between constituent proteins of whey protein.

Whey protein isolate (WPI) is mainly composed of ß-lactoglobulin (ß-LG), α-lactalbumin (α-LA) and bovine serum albumin (BSA). The aim of this study was to compare and analyze the influence of WPI and its three main constituent proteins, as well as proportionally reconstituted WPI (R-WPI) on resveratrol. It was found that the storage stability of resveratrol was protected by WPI, not affected by R-WPI, but reduced by individual whey proteins at 45°C for 30 days. The rank of accelerated degradation of resveratrol by individual whey proteins was BSA > α-LA > ß-LG. The antioxidant activity, localization of resveratrol and oxidation of carrier proteins were determined by ABTS, H2O2 assay, synchronous fluorescence, carbonyl and circular dichroism. The non-covalent interactions and disulfide bonds between constituent proteins improved the antioxidant activity of the R-WPI-resveratrol complex, the oxidation stability of the carrier and the solvent shielding effect on resveratrol, which synergistically inhibited the degradation of resveratrol in R-WPI system. The results gave insight into elucidating the interaction mechanism of resveratrol with protein carriers.

Changes in bone turnover markers and bone mineral density after radiofrequency ablation for mild primary hyperparathyroidism: a prospective cohort study.

Background: The application of radiofrequency ablation (RFA) is becoming increasingly widespread in the treatment of primary hyperparathyroidism (PHPT). However, the effect of RFA treatment on the skeleton in mild PHPT remains unclear. Therefore, the aim of this study was to investigate the change in bone turnover markers and bone mineral density (BMD) before and 2 years after RFA in patients with mild PHPT. Methods: In this open-label, prospective study, 81 patients with mild PHPT including 36 treated with RFA and 45 observed without intervention (OBS), along with 81 age-matched healthy controls, were enrolled from November 2018 to September 2021 at Gansu Provincial Hospital. The main outcome measures were levels of serum calcium, serum intact parathyroid hormone (iPTH), and bone turnover markers, including bone-specific alkaline phosphatase (ALP), C-terminal cross-linking telopeptides of type I collagen (ß-CTx), and osteocalcin (OC). BMD (femoral neck and lumbar spine) was measured with dual-energy X-ray absorptiometry, and spine radiographs were obtained for vertebral fracture assessment. Paired and unpaired two-tailed t-tests and Spearman rank correlation coefficient were used for statistical analyses. Results: Normalized outcomes for both iPTH and calcium levels were achieved in 32 of 36 (88.9%) patients with mild PHPT treated with RFA. There was a significant treatment effect of RFA on bone turnover biomarkers compared with OBS before the treatment (P=0.04) and at the end of follow-up or (P=0.03). BMD of the lumbar spine increased by 1.8% (P=0.03) and remained stable in the femoral neck (P=0.17) after RFA. However, there was an obvious treatment effect of RFA on BMD compared with OBS (P 0.04). The only compartment with a T-score increase in the RFA group was the lumbar spine in (P<0.001). There was no difference in fracture frequency between groups during the follow-up period. Conclusions: RFA can improve serum bone turnover markers in patients with mild PHPT and can be expected to increase BMD in the L1-L4 vertebrae and preserve BMD in the femoral neck. Whether RFA can reduce fracture risk in the long-term is a clinical concern for patients with mild PHPT.

Guanine-Rich RNA Sequence Binding Factor 1 Deficiency Promotes Colorectal Cancer Progression by Regulating PI3K/AKT Signaling Pathway.

Background: Guanine-rich RNA sequence binding factor 1 (GRSF1), part of the RNA-binding protein family, is now attracting interest due to its potential association with the progression of a variety of human cancers. The precise contribution and molecular mechanism of GRSF1 to colorectal cancer (CRC) progression, however, have yet to be clarified. Methods: Immunohistochemistry and Western Blot analysis was carried out to detect the expression of GRSF1 in CRC at both mRNA and protein levels and its subsequent effects on prognosis. A series of functional tests were performed to understand its influence on proliferation, migration, and invasion of CRC cells. Results: The universal downregulation of GRSF1 in CRC was identified, indicating a correlation with poor prognosis. Our functional studies unveiled that the elimination of GRSF1 enhances tumour activities such as proliferation, migration, and invasion of CRC cells, while GRSF1 overexpression curtailed these abilities. Conclusion: Notably, we uncovered that GRSF1 insufficiency modulates the PI3K/Akt signaling pathway and Ras activation in CRC. Therefore, our data suggest GRSF1 operates as a tumor suppressor gene in CRC and may offer promise as a potential biomarker and novel therapeutic target in CRC management.

Unveiling Major Histocompatibility Complex-mediated Pan-Cancer Immune Features by Integrated Single-Cell and Bulk RNA Sequencing.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet persistent challenges such as low response rate and significant heterogeneity necessitate attention. The pivotal role of the major histocompatibility complex (MHC) in ICI efficacy, its intricate impacts and potentials as a prognostic marker, warrants comprehensive exploration. This study integrates single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and spatial transcriptomic analyses to unveil pan-cancer immune characteristics governed by the MHC transcriptional feature (MHC.sig). Developed through scRNA-seq analysis of 663,760 cells across diverse cohorts and validated in 30 solid cancer types, the MHC.sig demonstrates a robust correlation between immune-related genes and infiltrating immune cells, highlighting its potential as a universal pan-cancer marker for anti-tumor immunity. Screening the MHC.sig for therapeutic targets using CRISPR data identifies potential genes for immune therapy synergy and validates its predictive efficacy for ICIs responsiveness across diverse datasets and cancer types. Finally, analysis of cellular communication patterns reveals interactions between C1QC+macrophages and malignant cells, providing insights into potential therapeutic agents and their sensitivity characteristics. This comprehensive analysis positions the MHC.sig as a promising marker for predicting immune therapy outcomes and guiding combinatorial therapeutic strategies.

Analysis of PIK3CA mutations in the primary and recurrent tumors of hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer.

OBJECTIVE: Our aim was to compare the PIK3CA mutation status in matched primary and recurrent tumors of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC) to gain insight into the optimization of patient selection and detection time for PIK3CA-targeted therapy. METHODS: The data were from 3035 patients with BC diagnosed at the Breast Disease Center, Peking University First Hospital, between January 2008 and December 2017. Matched primary and recurrent samples were profiled using amplification-refractory mutation system-polymerase chain reaction covering 11 mutational hotspots in PIK3CA. RESULTS: PIK3CA mutations were detected in 54.3% primary tumors and 48.6% corresponding recurrences. PIK3CA mutation was detected in 37.5% cases in the locoregional recurrent group and 40.0% of distant metastasis, without a statistical difference. Besides, PIK3CA mutations were concordant in 88.6% of the matched pairs. For patients treated with neoadjuvant chemotherapy, 100% concordance was observed. However, PIK3CA mutation was neither correlated with clinicopathological features nor associated with clinical outcomes. CONCLUSIONS: Mutations in PIK3CA in HR+/HER2- BC generally progressed to recurrent tumors. The high concordance rate of PIK3CA mutation status between primary tumors and corresponding recurrences suggests that the detection of primary tumors could be a substitute approach when recurrent samples are not easily obtainable.

Secofumitremorgins C and D, a pair of atropisomers from saltern-derived fungus Aspergillus fumigatus GXIMD00544.

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.

Associations of appendicular lean mass and abdominal adiposity with insulin resistance in older adults: A cross-sectional study.

Loss of lean muscle mass and accumulation of adipose tissue are changes associated with aging. Previous studies have documented various components of body composition as predictors for insulin resistance. The objective of this study was to investigate whether components of body composition-appendicular lean mass (ALM) and/or abdominal fat mass (AFM)-correlate with insulin resistance in older men and women. This was a cross-sectional study of 92 older men and women. Weight was classified according to body mass index (BMI)-normal (BMI <25), overweight (BMI 25-30), and obese (BMI >30). All body composition data was determined by dual energy x-ray absorptiometry (DEXA), and insulin resistance was assessed by the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable regression models with two-way interaction terms were employed to assess whether the associations between components of body composition and log HOMA varied by BMI categories. Adjusted regression showed that log HOMA was significantly associated with AFM (estimate ± standard error: 0.055 ± 0.026) and ALM (0.057 ± 0.029) for the overweight participants (p-values <0.05). Additionally, the adjusted associations between log HOMA and ALM were significantly greater for participants who were either obese or overweight compared to those with a normal BMI (p<0.002). Less consistent relationships were observed between insulin resistance and abdominal fat mass across BMI categories, whereas more consistent associations were observed between insulin resistance and appendicular lean mass in individuals with greater BMI. Further research is needed to clarify if lipid deposition within muscle tissue promotes muscle dysfunction and thereby increases risk for insulin resistance.

The impact of the health microinsurance M-FUND on the utilization of health services among migrant workers and their dependents in Thailand: A case-control study.

Background: Even though Thailand has launched multiple migrant health policies, migrants still face various barriers in accessing health care. To some extent, these barriers may be reduced by health microinsurance. The M-FUND is a low-cost, not-for-profit health protection scheme for migrant workers in Thailand, created by Dreamlopments Social Enterprise and Foundation to support sustainable access to quality healthcare services for migrants. We aimed to investigate the impact of the M-FUND on utilization of health services. Methods: Over a period of three months, we conducted quantitative face-to-face interviews with 408 M-FUND members, and 452 age, sex and location matched non-member controls in Tak Province, Thailand. We compared utilization of health services between members and non-members using logistic regression controlling for a number of socio-demographic variables and variables related to migration such as years in Thailand, legal status, etc. Findings: M-FUND members were more likely to have utilized outpatient services (adjusted odds ratio: 1·74, 95 % confidence interval: 1·24-2·44), inpatient services (2·96, 1.11-7·92), and emergency care (1·89, 0·78-4·56), although the latter was not statistically significant. Members were more likely not to have purchased medicines over-the-counter (1·67, 1·22-2·27) than non-members. Members were also more likely to have utilized any additional specific service during a consultation (2·31, 1·49-3·58) including any type of imaging method (2·62, 1·29-5·29) and blood tests (1·64, 0·99-2·71). There were some differences between men and women, but most were not statistically significant. Interpretation: The M-FUND health microinsurance was positively associated with the utilization of all major types of health services among migrant workers and their dependents in Thailand. For migrants, particularly vulnerable migrant workers and their dependents, the M-FUND appears to be a good approach to reducing barriers to health care. This study of the impact of health microinsurance for migrants provides important information for policy and program planners in the field of migrant health. However, more research is needed on health microinsurance schemes for migrants in different settings and for other underserved communities as well as the sex-specific impact on health service utilization.

Influences of lower pH on phytoplankton growth in alkaline lakes after water transfer: Insights from a coupled hydrodynamic-algal ecological model and experimental analysis.

Alkaline lakes with high pH and unique ecological communities often face water-level drawdown and ecological degradation problems due to climatic and hydrologic factors. Water transfer is becoming a popular method for solving these problems. However, a high pH is often considered the key to maintaining the stability of alkaliphilic algal communities, and a lower pH induced by water transfer from a neutral-pH river may threaten ecosystems in alkaline lakes. To explore the response characteristics of phytoplankton in alkaline lakes to pH changes, we conducted cultivation experiments on one species of dominant Cyanobacteria and one species of dominant Chlorophyta from alkaline lakes under different pH conditions. Subsequently, we constructed a coupled hydrodynamic and algal mathematical model considering the effect of pH to predict the dynamic changes in phytoplankton in a typical alkaline lake under water-transfer conditions. Both species are basophilic, and pH has a "low-inhibition and high-promotion" effect on their growth. A lower pH is detrimental to cyanobacterial growth and competitiveness, which may cause Cyanobacteria to lose their dominance in weakly alkaline environments with a pH < 8.5; additionally, water transfer causes a decrease in the total biomass and proportion of Cyanobacteria in Lake Chenghai, with decreases induced by pH changes accounting for 13.4% and 70.1%, respectively. The decrease in pH is the main reason for the decrease in dominance of Cyanobacteria after water transfer. These results provide a basic summary of the effects of pH changes on the algal growth in alkaline lakes and are a useful for formulating ecological water-transfer strategies for alkaline lakes.

Enhanced adsorption of phosphate by rice straw-based biochar prepared via metal impregnation and bio-template technology.

Phosphate removal from water through green, highly efficient technologies has received much attention. Biochar is an effective adsorbent for phosphate removal. However, adsorption capacity of phosphate on pristine rice straw-based biochar was not optimistic due to low anion exchange capacity. In this study, Fe-modified, Mg-modified and MgFe-modified rice straw-based biochar (Fe-BC, Mg-BC and MgFe-BC) were prepared by combining metal impregnation and biological template methods to improve the adsorption capacity of phosphate. The surface characteristics of biochar and the adsorption behavior of phosphate on biochar were investigated. The modified biochar had the specific surface area of 17.910-39.336 m2/g, and their surfaces were rich in a large number of functional groups and metal oxides. Phosphate release was observed on pristine rice straw-based biochar without metal impregnation. The maximum adsorption capacities of phosphate on MgFe-BC, Mg-BC and Fe-BC at 298 K were 6.93, 5.75 and 0.23 mg/g, respectively. Adsorption was a spontaneous endothermic process, while chemical adsorption dominated and electrostatic attraction and pores filling existed simultaneously. Based on the site energy distribution theory study, the standard deviation of MgFe-BC decreased from 6.96 to 4.64 kJ/mol with temperature increasing, which proved that the higher the temperature would cause the lower heterogeneity. Moreover, the effects of pH, humic acid, co-existing ions and ionic strength on phosphate adsorption of MgFe-BC were also discussed. MgFe-BC with fine pores and efficient adsorption sites is an ideal adsorbent for phosphate removal from water.

Exosomes secreted by adipose mesenchymal stem cells overexpressing circPIP5K1C exert.

BACKGROUND: Erectile dysfunction (ED) seriously affects men's normal life, and obstructive sleep apnoea (OSA) has been diagnosed as a causative factor. Currently, exosomes secreted by adipose mesenchymal stem cells (ADSC) have been used in the non-clinical experimental treatment of ED disease with prominent efficacy due to the advantages of high stability and no immune exclusion. METHODS: In this study, chronic intermittent hypoxia (CIH) exposure was used to induce ED-corresponding phenotypes in Sprague Dawley (SD) rats as well as in cavernous smooth muscle cells (CCSMCs). ED symptoms were treated using exosomes secreted by ADSCs overexpressing circPIP5K1C (EXO-circ) injected into the rat corpus cavernosum. RESULTS: EXO-circ has the effect of ameliorating ED induced by CIH exposure in rats, the mechanism of which is to promote the expression of the downstream target gene SMURF1 after adsorption of miR-153-3p through the sponge so that SMURF1 and PFKFB3 occur protein-protein binding and ubiquitination degradation of PFKFB3 appears to inhibit the occurrence of spongiotic smooth muscle cells glycolysis, and to restore the function of the smooth muscle. CONCLUSIONS: These findings show that EXO-circ have a promising therapeutic potential in OSA-induced ED.

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice.

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/ß-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

Calreticulin regulates the expression of MMP14 and ADAR1 through EIF2AK2 signaling to promote the proliferation and progression of malignant melanoma cells.

It has been demonstrated that calreticulin (CALR) is expressed abnormally in various tumors and is involved in the occurrence and development of tumors. In this study, CALR and EIF2AK2 expression was measured in the clinical specimens of 39 patients with melanoma. Then, we constructed knockdown and overexpression cell models of CALR and EIF2AK2 and used wound healing and Transwell assays to observe cell migration and invasion. Apoptosis, EDU, and ROS assays were used to measure cell apoptosis and proliferation, as well as ROS levels. The effect of CALR on endoplasmic reticulum stress was detected using endoplasmic reticulum fluorescent probes. Western blotting was used to detect protein levels of CALR, EIF2AK2, ADAR1, and MMP14. The results indicated that CALR and EIF2AK2 expression levels were significantly higher in human melanoma tissues than in adjacent non-tumor tissue. In addition, we found a correlation between CALR and the expression of EIF2AK2 and MMP14, and the experimental results indicated that overexpression of CALR significantly upregulated the expression of EIF2AK2, MMP14, and ADAR1, while knockdown of CALR inhibited their expression. Notably, the knockdown of EIF2AK2 in the CALR overexpression group blocked the upregulation of MMP14 and ADAR1 expression by CALR, and the knockdown of both CALR and EIF2AK2 significantly inhibited MMP14 and ADAR1 expression. In conclusion, CALR and EIF2AK2 play a promoting role in melanoma progression, and knockdown of CALR and EIF2AK2 may be an effective anti-tumor target, and its mechanism may be through MMP14, ADAR1 signaling.

[Ginsenoside Rg_1 ameliorates OGD/R-induced PC12 cell injury by inhibiting autography via IRE1-JNK-CHOP pathway].

This study investigated the protective effect of ginsenoside Rg_1(GRg_1) on oxygen and glucose deprivation/reoxygenation(OGD/R)-injured rat adrenal pheochromocytoma(PC12) cells and whether the underlying mechanism was related to the regulation of inositol-requiring enzyme 1(IRE1)-c-Jun N-terminal kinase(JNK)-C/EBP homologous protein(CHOP) signaling pathway. An OGD/R model was established in PC12 cells, and PC12 cells were randomly classified into control, model, OGD/R+GRg_1(0.1, 1, 10 µmol·L~(-1)), OGD/R+GRg_1+rapamycin(autophagy agonist), OGD/R+GRg_1+3-methyladenine(3-MA,autophagy inhibitor), OGD/R+GRg_1+tunicamycin(endoplasmic reticulum stress agonist), OGD/R+GRg_1+4-phenylbutyric acid(4-PBA, endoplasmic reticulum stress inhibitor), and OGD/R+GRg_1+3,5-dibromosalicylaldehyde(DBSA, IRE1 inhibitor) groups. Except the control group, the other groups were subjected to OGD/R treatment, i.e., oxygen and glucose deprivation for 6 h followed by reoxygenation for 6 h. Cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide(MTT) assay. Apoptosis was detected by Hoechst 33342 staining, and the fluorescence intensity of autophagosomes by the monodansylcadaverine(MDC) assay. Western blot was employed to determine the expression of autophagy-related proteins(Beclin1, LC3-Ⅱ, and p62) and the pathway-related proteins [IRE1, p-IRE1, JNK, p-JNK, glucose-regulated protein 78(GRP78), and CHOP]. The results showed that GRg_1 dose-dependently increased the viability of PC12 cells and down-regulated the expression of Beclin1, LC3-Ⅱ, p-IRE1, p-JNK, GRP78, and CHOP, compared with the model group. Furthermore, GRg_1 decreased the apoptosis rate and MDC fluorescence intensity and up-regulated the expression of p62 protein. Compared with the OGD/R+GRg_1(10 µmol·L~(-1)) group, OGD/R+GRg_1+rapamycin and OGD/R+GRg_1+tunicamycin groups showed increased apoptosis rate and MDC fluorescence intensity, up-regulated protein levels of Beclin1, LC3-Ⅱ, p-IRE1, p-JNK, GRP78, and CHOP, decreased relative cell survival rate, and down-regulated protein level of p62. The 3-MA, 4-PBA, and DBSA groups exerted the opposite effects. Taken together, GRg_1 may ameliorate OGD/R-induced PC12 cell injury by inhibiting autophagy via the IRE1-JNK-CHOP pathway.

Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

Pharmacological elevation of glutathione inhibits status epilepticus-induced neuroinflammation and oxidative injury.

Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP's ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.