Identification of methylation driver genes for predicting the prognosis of pancreatic cancer patients based on whole-genome DNA methylation sequencing technology.

This study was based on the use of whole-genome DNA methylation sequencing technology to identify DNA methylation biomarkers in tumor tissue that can predict the prognosis of patients with pancreatic cancer (PCa). TCGA database was used to download PCa-related DNA methylation and transcriptome atlas data. Methylation driver genes (MDGs) were obtained using the MethylMix package. Candidate genes in the MDGs were screened for prognostic relevance to PCa patients by univariate Cox analysis, and a prognostic risk score model was constructed based on the key MDGs. ROC curve analysis was performed to assess the accuracy of the prognostic risk score model. The effects of PIK3C2B knockdown on malignant phenotypes of PCa cells were investigated in vitro. A total of 2737 differentially expressed genes were identified, with 649 upregulated and 2088 downregulated, using 178 PCa samples and 171 normal samples. MethylMix was employed to identify 71 methylation-driven genes (47 hypermethylated and 24 hypomethylated) from 185 TCGA PCa samples. Cox regression analyses identified eight key MDGs (LEF1, ZIC3, VAV3, TBC1D4, FABP4, MAP3K5, PIK3C2B, IGF1R) associated with prognosis in PCa. Seven of them were hypermethylated, while PIK3C2B was hypomethylated. A prognostic risk prediction model was constructed based on the eight key MDGs, which was found to accurately predict the prognosis of PCa patients. In addition, the malignant phenotypes of PANC-1 cells were decreased after the knockdown of PIK3C2B. Therefore, the prognostic risk prediction model based on the eight key MDGs could accurately predict the prognosis of PCa patients.

Risk factors of recurrence after incisional hernia preperitoneal repair: a long-term retrospective single-center cohort study.

PURPOSE: To explore the risk factors for incisional hernia (IH) recurrence following open prepertioneal repair. METHODS: Patients diagnosed with primary IH who underwent open preperitoneal repair at our hospital were enrolled. Patients were assessed, and perioperative factors were collected. Recurrence surveys were performed at regular intervals throughout the long-term postoperative follow-up. The risk factors for IH recurrence were identified using univariate and multivariate analyses. RESULTS: This study included 145 patients. Significant differences were found between recurrence and non-recurrence patients regarding pulmonary ventilation function (PVT), age, body mass index (BMI), mesh materials, type of surgery (clean, clean-contaminated, or contaminated), surgical site infections (SSIs), maximum width of the hernia defect (MWHD), and site of incisional hernia (P < 0.01). The univariate survival analysis revealed that PVT abnormalities, age > 70 years, BMI > 27 kg/m2, porcine small intestine submucosal (PSIS) mesh, non-clean surgery, SSIs, MWHD > 10 cm, and location in the lateral zones were significant factors for IH recurrence after open preperitoneal repair. The multivariate survival analysis showed that PVT abnormalities, age > 70 years, BMI > 27 kg/m2, and PSIS mesh were independent risk factors for IH recurrence after open preperitoneal repair. CONCLUSIONS: We identified PVT abnormalities, age > 70 years, BMI > 27 kg/m2, and PSIS mesh as novel risk factors for IH recurrence after open preperitoneal repair.

Abrogation of KLF5 sensitizes BRCA1-proficient pancreatic cancer to PARP inhibition.

Poly ADP-ribose polymerase (PARP) inhibitor monotherapies are selectively effective in patients with pancreatic, breast, prostate, and ovarian cancers with BRCA1 mutations. Cancer patients with more frequent wild-type BRCA show poor responses to PARP inhibitors. Moreover, patients who are initially sensitive to these inhibitors eventually respond poorly to drugs. In the present study, we discover that abrogation of Kruppel-like factor 5 (KLF5) significantly inhibits homologous recombination, which is the main mechanism for DNA double-stranded repair. Furthermore, the downregulation of KLF5 expression promotes the DNA damage induced by olaparib and significantly reduces the IC 50 of the RARP inhibitor in pancreatic cancer cells. Overexpression of BRCA1 reverses the above effects caused by silencing of KLF5. Olaparib combined with a KLF5 inhibitor has an enhanced cytotoxic effect. Mechanistically, we identify BRCA1 as a KLF5 target gene. BRCA1 is positively correlated with KLF5 in PDAC tissue. Our results indicate that inhibition of KLF5 may induce BRCAness in a larger pancreatic cancer subset with proficient BRCA. The combination of KLF5 inhibitors and PARP inhibitors provides a novel treatment strategy to enhance the sensitivity of BRCA1-proficient pancreatic cancer to PARP inhibitors.

Construction of S100 family members prognosis prediction model and analysis of immune microenvironment landscape at single-cell level in pancreatic adenocarcinoma: a tumor marker prognostic study.

Pancreatic adenocarcinoma characterized by a mere 10% five-year survival rate, poses a formidable challenge due to its specific anatomical location, making tumor tissue acquisition difficult. This limitation underscores the critical need for novel biomarkers to stratify this patient population. Accordingly, this study aimed to construct a prognosis prediction model centered on S100 family members. Leveraging six S100 genes and their corresponding coefficients, an S100 score was calculated to predict survival outcomes. The present study provided comprehensive internal and external validation along with power evaluation results, substantiating the efficacy of the proposed model. Additionally, the study explored the S100-driven potential mechanisms underlying malignant progression. By comparing immune cell infiltration proportions in distinct patient groups with varying prognoses, the research identified differences driven by S100 expression. Furthermore, the analysis explored significant ligand-receptor pairs between malignant cells and immune cells influenced by S100 genes, uncovering crucial insights. Notably, the study identified a novel biomarker capable of predicting the sensitivity of neoadjuvant chemotherapy, offering promising avenues for further research and clinical application.

BMP6 inhibits gastric cancer growth and predicts good prognosis.

Background: Gastric cancer (GC) is a common tumors in the digestive tract, and effective treatment methods are still lacking. Bone morphogenetic protein 6 (BMP6) is closely related to the occurrence and development of various tumors, but its relevance to GC is still unclear. The aim of the study was to explore the relationship between BMP6 and the occurrence and development of GC. Methods: In this study, we investigated the relationship between BMP6 and the prognosis of GC patients using bioinformatics technology and clinical tissue samples. We also explored the connection between BMP6 and the biological behavior of GC cells through molecular biology experiments and relevant in vivo animal experiments. Finally, we examined the mechanisms by which BMP6 inhibits the onset and progression of GC. Results: Through analysis of The Cancer Genomics Atlas (TCGA) database, we observed that BMP6 is expressed at low levels in GC, and its low expression is associated with a poor prognosis in GC patients. Cell experiments demonstrated that BMP6 expression can influence the proliferation of GC cells both in vitro and in vivo. Furthermore, we discovered that BMP6 is linked to the nuclear factor-κB (NF-κB) pathway, and subsequent experiments confirmed that BMP6 can inhibit the biological activity of GC cells by activating the NF-κB pathway. Conclusions: Our findings suggest that BMP6 is a potential prognostic biomarker in GC and can regulate the biological activity of GC cells through the NF-κB pathway. BMP6 may serve as a promising therapeutic target for GC, and our study introduces novel ideas for the prevention and treatment of this disease.

Performance assessment of an injectable hyaluronic acid/polylactic acid complex hydrogel with enhanced biological properties as a dermal filler.

Injectable hyaluronic acid (HA) hydrogel plays an important role in dermal filling. However, conventional HA dermal fillers mostly lack bio-functional diversity and frequently cause adverse reactions because of the chemical stiffness of highly modified degree and crosslinker residues. In this study, polylactic acid (PLA) was embedded into HA hydrogel as a bioactive substance and 1,4-butanediol diglycidyl ether was used as a crosslinker to prepare the HA/PLA composite hydrogel with enhanced biocompatibility and biological performance. We aimed to investigate the properties of HA/PLA composite hydrogels as dermal fillers by assessing the rheological properties, surface microstructure, enzymolysis stability, swelling ratio, degradation rate, cytotoxicity, and anti-wrinkle effect on photo-aged skin. The results showed that the stability and stiffness of the composite hydrogel decreased with an increasing amount of PLA, while the in vivo safety of the HA/PLA hydrogel was enhanced, showing no adverse reactions such as edema, redness, or swelling. Moreover, the composite hydrogel with 2 wt% PLA exhibited excellent anti-wrinkle effects, showing the highest collagen production. Thus, the PLA-embedded HA composite hydrogel showed potential as a dermal filler with high safety, easy injectability, and excellent anti-wrinkle effects.

Involvement of PI3K/AKT Pathway in the Rapid Antidepressant Effects of Crocetin in Mice with Depression-Like Phenotypes.

The current first-line antidepressants have the drawback of slow onset, which greatly affects the treatment of depression. Crocetin, one of the main active ingredients in saffron (Crocus sativus L.), has been demonstrated to have antidepressant activities, but whether it has a rapid antidepressant effect remains unclear. This study aimed to investigate the onset, duration, and mechanisms of the rapid antidepressant activity of crocetin (20, 40 and 80 mg/kg, intraperitoneal injection) in male mice subjected to chronic restraint stress (CRS). The results of behavioral tests showed that crocetin exerted rapid antidepressant-like effect in mice with depression-like phenotypes, including rapid normalization of depressive-like behaviors within 3 h, and the effects could be maintained for 2 days. Hematoxylin-eosin (HE) and Nissl staining showed that crocetin ameliorated hippocampal neuroinflammation and nerve injuries in mice with depression-like phenotypes. The levels of inflammatory factors, corticosterone and pro brain-derived neurotrophic factor in crocetin-administrated mice serum were significantly reduced compared with those in the CRS group, as well as the levels of inflammatory factors in hippocampus. What's more, Western blot analyses showed that, compared to CRS-induced mice, the relative levels of mitogen-activated kinase phosphatase 1 and toll-like receptor 4 were significantly reduced after the administration of crocetin, and the relative expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP-response element binding protein, phosphorylated phosphoinositide 3 kinase (p-PI3K)/PI3K, phosphorylated protein kinase B (p-AKT)/AKT, phosphorylated glycogen synthase kinase 3ß (p-GSK3ß)/GSK3ß, phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR were markedly upregulated. In conclusion, crocetin exerted rapid antidepressant effects via suppressing the expression of inflammatory cytokines and the apoptosis of neuronal cells through PI3K/AKT signaling pathways. The rapid antidepressant effect of crocetin (40 mg/kg) could be maintained for at least 2 days after single treatment.

Enhancement of dissolution and oral bioavailability by adjusting microenvironment pH in crocetin ternary solid dispersions: Optimization, characterization, in vitro evaluation, and pharmacokinetics.

The most promising active ingredient of Crocus sativus L., crocetin (CCT), has been demonstrated to possess many biological activities. However, only a few studies have been conducted on CCT formulation, especially in oral formulation, mainly due to its insolubility in water, which limits its application for oral administration. This article reports an equilibrium saturation solubility and single-pass intestinal perfusion studies conducted to classify the biopharmaceutics classification system (BCS) of CCT. To enhance in vitro dissolution and in vivo oral bioavailability, ternary solid dispersions of CCT (CCT-SDs) with soluplus (SOL) as hydrophilic carrier and meglumine (MEG) as alkalizer were optimized using response surface methodology (RSM) with central composite design (CCD) experiments. Four different preparation methods were evaluated using the optimal formulation, including solvent evaporation, ball milling, spray drying, and freeze-drying. Prepared formulations were characterized by TG-DSC, FTIR, X-RPD, and SEM; the pharmacokinetic studies were performed in rats after oral administration. The cumulative dissolution rate of CCT-SDs containing SOL and MEG prepared by the ball milling method was 97.1% at 15 min and remained at 95.6% at 480 min, which was significantly higher than that of untreated CCT. The lower crystallinity, smaller particle size, and higher microenvironment pH (pHM) were observed in CCT-SDs prepared by the ball milling method. In vivo absorption of CCT-SDs (Cmax = 52.789 ± 12.441 µg/mL and AUC0-12 = 191.748 ± 35.043 µg/mL·h) was greater than untreated CCT (Cmax = 5.918 ± 1.388 µg/mL and AUC0-12 = 44.309 ± 7.264 µg/mL·h). In conclusion, the current study provides ternary solid dispersion formulation of CCT to increase the in vitro dissolution and in vivo bioavailability, which will benefit the commercial production and future clinical applications of CCT.

Electrodeposition of Self-Supported High-Entropy Spinel Oxides for Stable Oxygen Evolution.

Spinel oxides have attracted increasing interest due to their excellent activity in the oxygen evolution reaction (OER). However, despite the high intrinsic OER activity, their poor electrical conductivity and weak structural stability prevented their application for a long time. These shortcomings can be solved by effectively adjusting the electronic structures of spinel oxides through a high-entropy strategy. Herein, a rapid two-step method was developed to prepare self-supported high-entropy spinel-type oxides on a carbon cloth (CC) to yield (Fe0.2Co0.2Ni0.2Mn0.2Cr0.2)3O4@CC (abbreviated as FeCoNiMnCr@CC). The unique electronic structure and stable crystal configuration of the resulting FeCoNiMnCr@CC materials required only an overpotential of 287 mV for the OER at a current density of 10 mA cm-2 coupled with excellent cyclic stability. In summary, the proposed high-entropy strategy looks promising for improving the catalytic performance of spinel oxides.

MCC950 Ameliorates Acute Exogenous Lipoid Pneumonia Induced by Sewing Machine Oil in Rats via the NF-κB/NLRP3 Inflammasome Pathway.

BACKGROUND/AIM: Acute exogenous lipoid pneumonia (AELP) is a rare disorder caused by intake of lipid formulations and is often underdiagnosed. Meanwhile, the mechanism of AELP is still underlying. MCC950, was previously found to significantly suppress the release of inflammatory cytokines IL-18 and IL-1ß. However, the effect of MCC950 on AELP induced by sewing machine oil has not been reported. MATERIALS AND METHODS: The NLRP3, NF-[Formula: see text]B p65, caspase-1 and IL-1ß expression in lung tissues were compared between a rat model of AELP and control rats using western blotting and real-time quantitative assay. Moreover, haematoxylin and eosin (H&E) staining was performed to elucidate the mechanisms by which MCC950 ameliorates sewing machine oil-induced AELP in vivo. RESULTS: MCC950 reduced the expression of NF-[Formula: see text]B p65 in the lung samples of the treatment group and further down-regulated the NLRP3 and caspase-1 levels while inhibited the production of IL-1ß. Besides, decreases in inflammatory cell infiltration in the lung were shown using H&E staining. CONCLUSION: MCC950 ameliorates sewing machine oil-induced acute exogenous lipoid pneumonia in rats through inhibition of the NF-[Formula: see text]B/NLRP3 inflammasome pathway.

Prediction of future breakthroughs in materials synthesis and manufacturing techniques: a new perspective of synthesis dynamics theory.

The continuous development of different kinds of materials plays a significant role in social productivity. However, the lack of a complete synthesis kinetic theory has resulted in the absence of scientific guidance for the emergence of advanced manufacturing technologies, limiting the research and production of new types of materials. The present work aims at obtaining the basic form of the diffusion flux-driving force equation through the concept of ion diffusion so as to establish a synthesis kinetic theory. Using this theory, the scientific principles of existing synthesis technologies are summarized, and the key directions that future manufacturing technologies need to break through are proposed as well. Based on a comprehensive analysis of this theory, the feasible directions are discussed, providing strong support for the early realization of targeted design and manufacturing of new materials with specific functions.

Mendelian randomization study of thyroid function and anti-Müllerian hormone levels.

Objective: Although previous studies have reported an association between thyroid function and anti-Müllerian hormone (AMH) levels, which is considered a reliable marker of ovarian reserve, the causal relationship between them remains uncertain. This study aims to investigate whether thyrotropin (TSH), free thyroxine (fT4), hypo- and hyperthyroidism are causally linked to AMH levels. Methods: We obtained summary statistics from three sources: the ThyroidOmics Consortium (N = 54,288), HUNT + MGI + ThyroidOmics meta-analysis (N = 119,715), and the most recent AMH genome-wide association meta-analysis (N = 7,049). Two-sample MR analyses were conducted using instrumental variables representing TSH and fT4 levels within the normal range. Additionally, we conducted secondary analyses to explore the effects of hypo- and hyperthyroidism. Subgroup analyses for TSH were also performed. Results: MR analyses did not show any causality relationship between thyroid function and AMH levels, using normal range TSH, normal range fT4, subclinical hypothyroidism, subclinical hyperthyroidism and overt hypothyroidism as exposure, respectively. In addition, neither full range TSH nor TSH with individuals <50 years old was causally associated with AMH levels. MR sensitivity analyses guaranteed the robustness of all MR results, except for the association between fT4 and AMH in the no-DIO1+DIO2 group. Conclusion: Our findings suggest that there was no causal association between genetically predicted thyroid function and AMH levels in the European population.

Insights into high-entropy material synthesis dynamics criteria based on a thermodynamic framework.

High-entropy materials (HEMs) have attracted increasing research interests owing to their structural diversity and great potential for regulation. Numerous HEMs synthesis criteria have so far been reported but most are based on thermodynamics while a guiding basis for the synthesis of HEMs is lacking, resulting in many synthesis problems. Based on the overall thermodynamic formation criterion of HEMs, this study has explored the principles of the synthesis dynamics required based on this criterion and the influence of different synthesis kinetic rates on the final products of the reaction, filling the gap suggesting that thermodynamic criteria cannot guide the specific process changes. This will effectively provide more specific guidelines for the top-level design of material synthesis. By considering various aspects of HEMs synthesis criteria, new technologies suitable for high-performance HEMs catalysts were extracted. Also, the physical and chemical characteristics of the HEMs obtained from actual synthesis can be predicted in a better way, playing an important role in the personalized customization of HEMs with specific performance. Future development directions of HEMs synthesis were prospected for possible prediction and customization of HEMs catalysts with high performance.

Reasonably optimized structure of iron-doped cobalt hydroxylfluoride for high-performance supercapacitors.

Cobalt hydroxylfluoride (CoOHF) is an emerging supercapacitor material. However, it remains highly challenging to effectively enhance the performance of CoOHF, which is limited by its poor electron and ion transport ability. In this study, the intrinsic structure of CoOHF was optimized through Fe doping (CoOHF-xFe, where x represents the Fe/Co feeding ratio). As indicated by the experimental and theoretical calculation results, the incorporation of Fe effectively enhances the intrinsic conductivity of CoOHF and optimizes its surface ion adsorption capacity. Moreover, since the radius of Fe is slightly larger than that of Co, the space between the crystal planes of CoOHF increases to a certain extent, and the ability to store ions is consequently enhanced. The optimized CoOHF-0.06Fe sample exhibits the maximum specific capacitance (385.8 F g-1). The asymmetric supercapacitor with activated carbon achieves a high energy density of 37.2 Wh kg-1 at a power density of 1600 W kg-1, and a full hydrolysis pool is successfully driven by the device, indicating great application potential. This study lays a solid basis for the application of hydroxylfluoride to a novel generation of supercapacitors.

MicroRNA-92a-3p Inhibits Cell Proliferation and Invasion by Regulating the Transcription Factor 21/Steroidogenic Factor 1 Axis in Endometriosis.

Endometriosis (EMS) is an estrogen-dependent disease. However, little is known about the regulation of estrogen, a potential therapeutic target, in EMS, which remains very poorly managed in the clinic. We hypothesized that microRNAs (miRNAs) can be exploited therapeutically to regulate transcription factor 21 (TCF21) and steroidogenic factor-1 (SF-1) gene expression. In our study, paired eutopic and ectopic endometrial samples were obtained from women with EMS and processed by a standard protocol to obtain human endometrial stromal cells (EMs) for in vitro studies. We found that miR-92a-3p levels were decreased in ectopic endometrium and ectopic stromal cells (ESCs) compared with paired eutopic lesions. miR-92a-3p overexpression significantly suppressed the proliferation and migration of ESCs, whereas a decreased level of miR-92a-3p generated the opposite results. Next, we identified TCF21 as a candidate target gene of miR-92a-3p. In vitro cell experiments showed that miR-92a-3p negatively regulated the expression of TCF21 and its downstream target gene SF-1. Moreover, cell proliferation and invasion ability decreased after the silencing of SF-1 and increased after SF-1 overexpression. We also observed that silencing SF-1 while inhibiting miR-92a-3p partially blocked the increase in cell proliferation and invasion ability caused by miR-92a-3p knockdown while overexpressing both SF-1 and miR-92a-3p mitigated the impairment in cell proliferation and invasion ability caused by miR-92a-3p overexpression. Our results may provide a novel potential therapeutic target for the treatment of EMS.

Crocetin confers neuroprotection and is anti-inflammatory in rats with induced glaucoma.

BACKGROUND: Crocetin is a bioactive ingredient in saffron, derived from the Crocus sativus stigmas of the Iridaceae family. As a chemically carotenoid derivative, crocetin exhibites effects like anti-inflammatory, antioxidant, neuroprotective, etc. However, the protective effect of crocetin on glaucoma and its mechanism remains unclear. The current study assesed the neuroprotective and anti-inflammatory effects of crocetin on retinal neurons in glaucoma rats which were induced by 0.3% carbomer injection into the anterior chamber. METHODS AND RESULTS: The pathological structures on the retina and optic nerve were observed and examined by H&E staining and transmission electron microscopy. Immunohistochemical staining was used to detect the expression of TNF-α, IL-1ß, and IL-6 of the retina and the expression of a brain-derived neurotrophic factor (BDNF) in the primary visual cortex (PVC). Western blot was carried out to detect the expression of PI3K, Akt, and NF-κB in the retina. It was found that crocetin ameliorated the pathological changes of the retina and ON and reduced the number of apoptotic retinal ganglion cells. Immunohistochemical staining showed that crocetin could decrease the contents of TNF-α, IL-1ß, and IL-6 and increase the contents of BDNF. Western blot showed that crocetin was found to suppress the expression of PI3K, Akt, and NF-κB. CONCLUSION: The results obtained in this study have indicated that crocetin showes neuroprotective effects on retinal ganglion cells in glaucoma rats and inhibits retinal dysfunction. Meanwhile, crocetin exerted an anti-inflammatory effect to protect the retina by inhibiting the expression of the PI3K/Akt/NF-κB signaling pathway. This work provides substantial evidence that crocetin may be a potential drug for the treatment of glaucoma.

Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, the dried stigma of Crocus sativus L., has a long history of use in the treatment of depression in traditional Chinese medicine and Islamic medicine. The unique aroma of saffron, primarily derived from its volatile oil, has been widely used by folk to mitigate anxiety and depression via sniffing because the aroma of saffron has a pleasant and invigorating effect. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect and the underlying mechanism of saffron essential oil (SEO) in mice exposed to chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: In this study, compounds of SEO were identified using gas chromatography-mass spectrometry analysis, while network pharmacology was used to predict potential active compounds, antidepressant targets, and related signaling pathways of SEO. The CUMS depression model was further used to explore the therapeutic effect and possible mechanism of SEO. During the modeling period, mice were regularly administered fluoxetine (3.6 mg/kg, i.g.) or diluted SEO (2%, 4%, and 6% SEO, inhalation). The antidepressant and neuroprotective effects of SEO were evaluated by behavior tests (the open field test, the sucrose preference test, the tail suspension test, and the forced swimming test), hematoxylin-eosin staining, and Nissl staining. The enzyme-linked immunosorbent assay kits were used to measure dopamine (DA), 5-serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and γ-aminobutyric acid (GABA) levels in serum. The relative abundance of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B in the hippocampus was determined using western blot (WB). RESULTS: According to the network pharmacology analysis, seven active SEO compounds mediated 113 targets related to depression treatment, most of which were enriched in the 5-HT synapse, calcium signaling pathway, and cAMP signaling pathway. In vivo experiments indicated that fluoxetine and SEO improved depression-like behaviors in depressed mice. The levels of 5-HT, DA, BDNF, and GABA in serum increased significantly. Histopathological examinations revealed that fluoxetine and SEO ameliorated neuronal damage in the hippocampus. WB analysis showed that the relative expressions of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B were significantly higher in the fluoxetine and SEO groups than in the CUMS group. CONCLUSION: Overall, these findings suggest that SEO significantly alleviates the depressive symptoms in CUMS exposed mice and partially restores hippocampal neuronal damage. Meanwhile, the best efficacy was observed in 4% SEO. Furthermore, the antidepressant mechanism of SEO is primarily dependent on the regulation of the MAPK-CREB1-BDNF signaling pathway.

Inactivated Covid-19 vaccine did not undermine live birth and neonatal outcomes of women with frozen-thawed embryo transfer.

STUDY QUESTION: Does inoculation with inactivated vaccines against coronavirus disease 2019 (Covid-19) before frozen-thawed embryo transfer (FET) affect live birth and neonatal outcomes? SUMMARY ANSWER: Inactivated Covid-19 vaccines did not undermine live birth and neonatal outcomes of women planning for FET. WHAT IS KNOWN ALREADY: Accumulating reports are now available indicating the safe use of mRNA vaccines against Covid-19 in pregnant and lactating women, and a few reports indicate that they are not associated with adverse effects on ovarian stimulation or early pregnancy outcomes following IVF. Evidence about the safety of inactivated Covid-19 vaccines is very limited. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis from Reproductive Medical Center of a tertiary teaching hospital. Clinical records and vaccination record of 2574 couples with embryos transferred between 1 March 2021 and 30 September 2021 were screened for eligibility of this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical and vaccination data of infertile couples planning for FET were screened for eligibility of the study. The reproductive and neonatal outcomes of FET women inoculated with inactivated Covid-19 vaccines or not were compared. The primary outcomes were live birth rate per embryo transfer cycle and newborns' birth height and weight. Secondary outcomes included rates of ongoing pregnancy, clinical pregnancy, biochemical pregnancy and spontaneous miscarriage. Multivariate logistical regression and propensity score matching (PSM) analyses were performed to minimize the influence of confounding factors. Subgroup analyses, including single dose versus double dose of the vaccines and the time intervals between the first vaccination and embryo transfer, were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: Vaccinated women have comparable live birth rates (43.6% versus 45.0% before PSM, P = 0.590; and 42.9% versus 43.9% after PSM, P = 0.688), ongoing pregnancy rates (48.2% versus 48.1% before PSM, P = 0.980; and 52.2% versus 52.7% after PSM, P = 0.875) and clinical pregnancy rate (55.0% versus 54.8% before PSM, P = 0.928; and 54.7% versus 54.2% after PSM, P = 0.868) when compared with unvaccinated counterparts. The newborns' birth length (50.0 ± 1.6 versus 49.0 ± 2.9 cm before PSM, P = 0.116; and 49.9 ± 1.7 versus 49.3 ± 2.6 cm after PSM, P = 0.141) and birth weight (3111.2 ± 349.9 versus 3030.3 ± 588.5 g before PSM, P = 0.544; and 3053.8 ± 372.5 versus 3039.2 ± 496.8 g after PSM, P = 0.347) were all similar between the two groups. Neither single dose nor double dose of vaccines, as well as different intervals between vaccination and embryo transfer showed any significant impacts on reproductive and neonatal outcomes. LIMITATIONS, REASONS FOR CAUTION: The main findings might be limited by retrospective design. Besides, inoculations of triple dose of Covid-19 vaccines were not available by the time of data collection, thus the results cannot reflect the safe use of triple dose of inactivated Covid-19 vaccines. Finally, history of Covid-19 infection was based on patients' self-report rather than objective laboratory tests. WIDER IMPLICATIONS OF THE FINDINGS: Eligible individuals of inactivated vaccines against Covid-19 should not postpone vaccination plan because of their embryo transfer schedule, or vice versa. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Medical Key Discipline of Guangzhou (2021-2023). All authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Detection of the role of intestinal flora and tryptophan metabolism involved in antidepressant-like actions of crocetin based on a multi-omics approach.

RATIONALE: Depression is a serious mood disorder, and crocetin has a variety of pharmacological activities, including antidepressant effect. The alterations of intestinal flora have a significant correlation with depression, and crocetin can alter the composition of intestinal flora in mice with depression-like behaviors. OBJECTIVE: This study investigated the underlying antidepressant mechanisms of crocetin through multi-omics coupled with biochemical technique validation. METHODS: Chronic unpredictable stress (CUMS) was used to induce mice model of depression to evaluate the antidepressant effect of crocetin through behavioral tests, and the metagenomic and metabolomic were used to explore the potential mechanisms involved. In order to verify its underlying mechanism, western blot (WB), Elisa, immune histological and HPLC techniques were used to detect the level of inflammatory cytokines and the level of metabolites/proteins related to tryptophan metabolism in crocetin-treated mice. RESULTS: Crocetin ameliorated depression-like behaviors and increased mobility in depressive mice induced by CUMS. Metagenomic results showed that crocetin regulated the structure of intestinal flora, as well as significantly regulated the function gene related to derangements in energy metabolism and amino acid metabolism in mice with depression-like behaviors. Metabolomic results showed that the tryptophan metabolism, arginine metabolism and arachidonic acid metabolism played an essential role in exerting antidepressant-like effect of crocetin. According to multi-omics approaches and validation results, tryptophan metabolism and inflammation were identified and validated as valuable biological processes involved in the antidepressant effects of crocetin. Crocetin regulated the tryptophan metabolism in mice with depression-like behaviors, including increased aryl hydrocarbon receptor (AhR) expression, reduced indoleamine 2,3-dioxygenase 1 (IDO1) and serotonin transporter (SERT) expression in the hippocampus, elevated the content of 5-HT, kynurenic acid in serum and 5-HT, tryptophan in hippocampus. In addition, crocetin also attenuated inflammation in mice with depression-like behaviors, which presented with reducing the production of inflammatory cytokines in serum and colon. Meanwhile, crocetin up-regulated the expression of zonula occludens 1 (ZO-1) and occludin in ileum and colon to repair the intestinal barrier for preventing inflammation transfer. CONCLUSION: Our findings clarify that crocetin exerted antidepressant effects through its anti-inflammation, repairment of intestinal barrier, modulatory on the intestinal flora and metabolic disorders, which further regulated tryptophan metabolism and impacted mitogen-activated protein kinase (MAPK) signaling pathway to enhance neural plasticity, thereby protect neural.