Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.

Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis.

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii served as key components of fecal microbiota transplantation to alleviate colitis.

Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. 40 donors were divided into high (donor-H) and low (donor-L) groups according to diversity and the abundance of Bacteroides and Faecalibacterium by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with group donor-H (p <0.05). Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy (p <0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group (p <0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, B. thetaiotaomicron and F. prausnitzii, as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs.

Association of lipoprotein lipase (LPL) gene variants with hyperlipidemic acute pancreatitis in southeastern Chinese population.

Objective: The study aims to explore the relationship between lipoprotein lipase (LPL) variants and hyperlipidemic acute pancreatitis (HLAP) in the southeastern Chinese population. Subjects and methods: In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the LPL gene were sequenced. The correlations between variants and phenotypes were also analysed. Results: The rate of rare LPL variants in the HLAP group is 14.81% (8 of 54), higher than in controls. Among the detected four variants (rs3735959, rs371282890, rs761886494 and rs761265900), the most common variant was rs371282890. Further analysis demonstrated that subjects with rs371282890 "GC" genotype had a 2.843-fold higher risk for HLAP (odds ratio [OR]: 2.843, 95% confidence interval [CI]: 1.119-7.225, p = 0.028) than subjects with the "CC" genotype. After adjusting for sex, the association remained significant (adjusted OR: 3.083, 95% CI: 1.208-7.869, p = 0.018). Subjects with rs371282890 "GC" genotype also exhibited significantly elevated total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels in all the participants and the HLAP group (p < 0.05). Conclusion: Detecting rare variants in LPL might be valuable for identifying higher-risk patients with HLAP and guiding future individualised therapeutic strategies.

Swine pseudorabies virus attenuated vaccine reprograms the kidney cancer tumor microenvironment and synergizes with PD-1 blockade.

The global incidence rate of kidney cancer (KC) has been steadily increasing over the past 30 years. With the aging global population, kidney cancer has become an escalating concern that necessitates vigilant surveillance. Nowadays, surgical intervention remains the optimal therapeutic approach for kidney cancer, while the availability of efficacious treatments for advanced tumors remains limited. Oncolytic viruses, an emerging form of immunotherapy, have demonstrated encouraging anti-neoplastic properties and are progressively garnering public acceptance. However, research on oncolytic viruses in kidney cancer is relatively limited. Furthermore, given the high complexity and heterogeneity of kidney cancer, it is crucial to identify an optimal oncolytic virus agent that is better suited for its treatment. The present study investigates the oncolytic activity of the Pseudorabies virus live attenuated vaccine (PRV-LAV) against KC. The findings clearly demonstrate that PRV-LAV exhibits robust oncolytic activity targeting KC cell lines. Furthermore, the therapeutic efficacy of PRV-LAV was confirmed in both a subcutaneous tumor-bearing nude mouse model and a syngeneic mouse model of KC. Combined RNA-seq analysis and flow cytometry revealed that PRV-LAV treatment substantially enhances the infiltration of a diverse range of lymphocytes, including T cells, B cells, macrophages, and NK cells. Additionally, PRV-LAV treatment enhances T cell activation and exerts antitumor effects. Importantly, the combination of PRV-LAV with anti-PD-1 antibodies, an approved drug for KC treatment, synergistically enhances the efficacy against KC. Overall, the discovery of PRV-LAV as an effective oncolytic virus holds significant importance for improving the treatment efficacy and survival rates of KC patients.

SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.

SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH levels.SBFI26 dose-dependently up-regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.

α-Glucosidase Inhibitory Phytochemical Components of Chinese Endemic Plant Whitfordiodendron filipes var. tomentosum.

Whitfordiodendron filipes var. tomentosum is an endemic plant in China. There have been no chemical or pharmacological studies of this plant reported before. In the current research, eight triterpenes and two steroids were obtained. Their structures were established by the analysis of NMR data and comparison with those reported in the literature. These ten structurally diverse compounds comprised five distinct carbon frameworks with different functionalities. The chemotaxonomic significance of these secondary metabolites was discussed, disclosing the common components between the variant W. filipes var. tomentosum and the species W. filipe. Evaluation of α-glucosidase inhibitory activities of these isolates disclosed that compounds 1, 2, 4, and 6 exhibited significant α-glucosidase inhibitory activities (IC50 = 16.6-19.2 µM), which were close in value to the positive control acarbose (IC50 = 11.5 µM). Moreover, the binding modes between the biologically active compounds 1, 2, 4, and 6 and the α-glucosidase protein were preliminarily studied using molecular docking. This study not only showed the chemical and biological profile of the plant W. filipes var. tomentosum but also revealed that these components could be developed as hypoglycemic lead compounds.

Influence of cancer-directed surgery on the prognosis of liver metastases from gastric cancer

There are controversial about the application of cancer-directed surgery (CDS) in patients with liver metastases from gastric cancer, with improved responses to chemotherapy and targeted treatments, the role of CDS in metastatic gastric cancer to the liver needs to be revisited. This study aimed to evaluate the effect of CDS on patients with liver metastases from gastric cancer. Data for patients with liver metastases from gastric cancer were extracted from the population-based Surveillance, Epidemiology, and End Results (SEER) database. A total of 958 individuals were enrolled, 285 in the CDS group and 673 in the non-cancer guided surgery (Non-CDS) group. Following propensity score matching (PSM) analysis at 1:1 in the two groups,285 were included in the survival analysis for each group. Kaplan–Meier values and Cox proportional risk models were used to estimate the effect of CDS on patients' prognoses. Compared with the Non-CDS group, the CDS group significantly prolonged the median overall survival from 4 months (95% confidence interval [CI] 3–5) to 11 months (95% CI 8–12), p value < 0.001. Overall survival (OS) at 1 year was higher in the CDS group than in the Non-CDS group, at 44% (95 CI 38–50) and 25% (95 CI 20–30), respectively. OS at 3 years was also higher in the CDS group than in the Non-CDS group, at 24% (95 CI 19–29) and 6% (95 CI 3–9), respectively. Multivariate analysis showed that Non-CDS (hazard ratio[HR] = 2.26, 95% CI 1.88–2.72, p value < 0.001) was an adverse independent prognostic factor for patients (AU)

1,2,3-Thiadiazole as a Modifiable and Scalable Directing Group for ortho-C-H Functionalization.

In the last few decades, directed C-H bond functionalization has had enormous applicability in academia and industry. The development of a novel, readily accessible, and scalable directing group with modifiable ability is highly desirable in C-H functionalization. Herein, we report the 1,2,3-thiadiazole as a modifiable directing group for C-H amidation and alkynylation with dioxazolones, p-toluenesulfonyl azide, and bromoalkynes in high yield. The densely functionalized 1,2,3-thiadiazole products are modified into thioamide, multisubstituted furan, γ-thiapyrone, thiazole, and various alkynyl sulfides through simple and one-step reactions. The competition experiments reveal that the directing ability of 1,2,3-thiadiazole is slightly weaker than pyridine and bidentate amide but stronger than the widely used carboxylate.

Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.

Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

Enhancing diabetic wound healing: advances in electrospun scaffolds from pathogenesis to therapeutic applications.

Diabetic wounds are a significant subset of chronic wounds characterized by elevated levels of inflammatory cytokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). They are also associated with impaired angiogenesis, persistent infection, and a high likelihood of hospitalization, leading to a substantial economic burden for patients. In severe cases, amputation or even mortality may occur. Diabetic foot ulcers (DFUs) are a common complication of diabetes, with up to 25% of diabetic patients being at risk of developing foot ulcers over their lifetime, and more than 70% ultimately requiring amputation. Electrospun scaffolds exhibit a structural similarity to the extracellular matrix (ECM), promoting the adhesion, growth, and migration of fibroblasts, thereby facilitating the formation of new skin tissue at the wound site. The composition and size of electrospun scaffolds can be easily adjusted, enabling controlled drug release through fiber structure modifications. The porous nature of these scaffolds facilitates gas exchange and the absorption of wound exudate. Furthermore, the fiber surface can be readily modified to impart specific functionalities, making electrospinning nanofiber scaffolds highly promising for the treatment of diabetic wounds. This article provides a concise overview of the healing process in normal wounds and the pathological mechanisms underlying diabetic wounds, including complications such as diabetic foot ulcers. It also explores the advantages of electrospinning nanofiber scaffolds in diabetic wound treatment. Additionally, it summarizes findings from various studies on the use of different types of nanofiber scaffolds for diabetic wounds and reviews methods of drug loading onto nanofiber scaffolds. These advancements broaden the horizon for effectively treating diabetic wounds.

Free total rhubarb anthraquinones protect intestinal mucosal barrier of SAP rats via inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhubarb is the peeled and dried roots of Rheum palmatum L. and Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. Free total rhubarb anthraquinones (FTRAs) were isolated and extracted from rhubarb. Previous studies have revealed that the early administration of FTRAs protects the intestinal mucosal barrier in rats with severe acute pancreatitis (SAP), the mechanism of which is not yet clear. However, we observed an enhanced expression of intestinal pyroptotic factors in rats treated with SAP, which may be related to the mechanism of intestinal barrier protection by FTRAs. AIM OF THE STUDY: The main objective of this study was to investigate the mechanism by which FTRAs protect the intestinal mucosal barrier in SAP rats, focusing on the classical pyroptosis pathway. MATERIALS AND METHODS: SAP was induced in rats through retrograde injection of sodium taurocholate via the pancreaticobiliary duct. Subsequently, FTRAs (22.5, 45, and 90 mg/kg), rhubarb (900 mg/kg, positive control), and saline (control) were administered at 0 h (immediately), 12 h, and 24 h post-surgery. Pancreatic and intestinal tissue injury, positive PI staining rate, and expression levels of various factors in intestinal tissues were compared across different groups. These factors include diamine oxidase (DAO), lactate dehydrogenase (LDH), high mobility group box chromosomal protein 1(HMGB1) and pro-inflammatory factors in intestinal and serum, pyroptosis-associated factors, toll-like receptor 4 (TLR-4), nuclear factor kappa-B (NF-kB), apoptosis-associated speck-like protein (ASC), NOD-like receptor protein 3 (NLRP3), cysteine protease-1 (caspase-1) and Gasdermin (GSDMD). RESULTS: The findings indicated that FTRAs protected the damaged intestine and pancreas and restored the expression of intestinal epithelial junction proteins in SAP rats. Additionally, it reduced intestinal and serum levels of DAO, interleukin 1, interleukin 18, HMGB1, and LDH, attenuated intestinal Positive PI staining rate, and significantly decreased the expressions of TLR-4, NF-kB, ASC, NLRP3, caspase-1 and GSDMD in SAP rats. CONCLUSIONS: The results suggest that FTRAs inhibited pyroptosis through down-regulation of the NLRP3-Caspase-1-GSDMD and TLR-4- NF-kB signaling pathways of intestinal tissues., thereby protecting the intestinal barrier of SAP rats.

Chrysophanol induces apoptosis and ferroptosis of gastric cancer cells by targeted regulation of mTOR.

Programmed cell death (PCD) induction is a promising strategy for killing gastric cancer cells. In this study, we investigated the effects of chrysophanol on apoptosis and ferroptosis in gastric cancer cells. Chrysophanol in concentrations ranging from 0 to 100 µM were used to treat GES-1, HGC-27 and AGS cells. Cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, JC-1 probe insertion, dihydroethidium staining and western blotting were performed. The effects of chrysophanol on gastric cancer cells were evaluated in vivo using a xenograft mouse model. Chrysophanol had no cytotoxic effects on GES-1 cells. Chrysophanol with concentrations higher than 25 µM inhibited gastric cancer cell colony formation and proliferation. Chrysophanol induces gastric cancer cell apoptosis in a dose-dependent manner, accompanied by mitochondrial membrane potential dysfunction and cytochrome c release. Additionally, chrysophanol increased the levels of reactive oxygen species, total iron, and Fe2+ in HGC-27 and AGS cells, in a dose-dependent manner. Treatment of cells with the ferroptosis inhibitor ferrostatin-1 attenuated the effects of chrysophanol on cell survival and the expression of ferroptosis markers SLC7A11 and GPX4. Screening by GEO software indicated that the mTOR signalling pathway is possibly regulated by chrysophanol. Furthermore, mTOR overexpression significantly reversed the inhibitory effects of chrysophanol on gastric cancer cells. In gastric cancer xenograft mouse models, chrysophanol treatment inhibited tumour growth and downregulated SLC7A11 and GPX4. Chrysophanol induces apoptosis and ferroptosis, making it a potential candidate for killing gastric cancer cells. The beneficial effects of chrysophanol may be attribute to the targeted regulation of mTOR.

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3.

To provide a theoretical basis for the prevention and treatment of atherosclerosis (AS), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on regulating the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMC) via sirtuin-1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) through Nedd4-like E3 ubiquitin-protein ligase WWP2 (WWP2). Here, Based on the establishment of ApoE-/- mouse models of high Hcy As and the model of Hcy stimulation of VSMC in vitro to observe the interaction between WWP2 and STAT3 and its effect on the proliferation, migration, and phenotypic transformation of Hcy-induced VSMC, which has not been previously reported. This study revealed that WWP2 could promote the proliferation, migration, and phenotype switch of Hcy-induced VSMC by up-regulating the phosphorylation of SIRT1/STAT3 signaling. Furthermore, Hcy might up-regulate WWP2 expression by inhibiting histone H3K27me3 expression through up-regulated UTX. These data suggest that WWP2 is a novel and important regulator of Hcy-induced VSMC proliferation, migration, and phenotypic transformation.

Association of blood parameters in early pregnancy with anemia during late pregnancy: a multicenter cohort study in China.

BACKGROUND: Low-hemoglobin concentration and anemia are important risk factors for the health and development of women and children. The aim of this study was to investigate the correlation between blood indicators in early pregnancy among non-anemia women and anemia in the third trimester among pregnant women in China with uncomplicated pregnancies >36 weeks. METHODS: This was a multicenter, prospective cohort study. Pregnant women registered at the survey hospitals from May 2019 to December 2020 were included and followed up until delivery and discharge. The predictive value of serum ferritin (SF) and routine blood indexes (platelet count, red blood cell count, hemoglobin level, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration) were analyzed using a receiver operating characteristic (ROC) curve for the occurrence of anemia in the third trimester. RESULTS: The area under the ROC curve of the first trimester hemoglobin for predicting anemia during late pregnancy (cutoff value 128 g/L, sensitivity 82.3%, specificity 49.6%) and iron deficiency anemia (cutoff value 124 g/L, sensitivity 66.3%, specificity 66.4%) in the third trimester was larger than those of other blood variables. CONCLUSIONS: Hemoglobin levels in the first trimester were significantly better predictors of anemia during the third trimester than the other indices. Our study contributes to the clinical practice of early intervention for anemia, thus taking effective measures to improve maternal and infant outcomes.

Characteristics of bone metabolism in the male patients with diabetic neuropathy.

BACKGROUND: This study aimed to evaluate the characteristics of bone metabolism and fracture risk in the type 2 diabetes mellitus (T2DM) patients with distal symmetric polyneuropathy (DSPN). METHODS: A total of 198 T2DM individuals were recruited from January 2017 to December 2020. Patients with DSPN were evaluated by strict clinical and sensory thresholds. Biochemical parameters and bone mineral density (BMD) were measured. The BMD, bone turnover markers, and probability of fracture were compared between two groups, and the factors related to BMD and probability of hip fracture in 10 years were further explored. RESULTS: Compared with type 2 diabetes mellitus without distal symmetric polyneuropathy (T2DN-) patients, type 2 diabetes mellitus with distal symmetric polyneuropathy (T2DN+) patients had lower level of cross-linked C-telopeptide (CTX) (0.32 ± 0.19 vs 0.38 ± 0.21 ng/mL, p = 0.038) and higher level of bone-specific alkaline phosphatase (BALP) (15.28 ± 5.56 vs 12.58 ± 4.41 µg/mL, p = 0.003). T2DN+ patients had higher BMD of lumbar L1-L4 (1.05 ± 0.19 vs 0.95 ± 0.37, p = 0.027) and higher probability of hip fracture (0.98 ± 0.88 vs 0.68 ± 0.63, p = 0.009) as compared to T2DN- individuals. Univariate correlation analysis showed that BALP level (coefficient (coef) = -0.054, p = 0.038), CTX level (coef = -2.28, p = 0.001), and hip fracture risk (coef = -1.02, p < 0.001) were negatively related to the BMD of L1-L4. As for the risk of hip fracture evaluated by WHO Fracture Risk Assessment Tool (FRAX), age (coef = 0.035, p < 0.001), use of insulin (coef = 0.31, p =0.015), and levels of BALP (coef = 0.031, p = 0.017) and CTX (coef = 0.7, p = 0.047) were positively related to the risk of hip fracture. Multivariate regression analysis showed that CTX level (coef = -1.41, p = 0.043) was still negatively related to BMD at the lumbar spine. CONCLUSION: This study indicates that T2DM patients with DSPN have special bone metabolism represented by higher BALP level and lower CTX level which may increase BMD at the lumbar spine.

Melatonin alleviates the toxic effect of di(2-ethylhexyl) phthalate on oocyte quality resulting from CEBPB suppression during primordial follicle formation.

Presently, the exposure of plasticizers to humans and animals occurs daily, which pose a potential threat to reproductive health. In the present study, a pregnant mouse model exposed to di(2-ethylhexyl) phthalate (DEHP, one of the most common plasticizers) and melatonin was established, and the single-cell transcriptome technology was applied to investigate the effects of melatonin in ovarian cells against DEHP. Results showed that DEHP markedly altered the gene expression pattern of ovarian cells, and severely weakened the histone methylation modification of oocytes. The administration of melatonin recovered the expression of LHX8 and SOHLH1 proteins that essential for primordial follicle formation, and increased the expression of CEBPB, as well as key genes of histone methylation modification (such as Smyd3 and Kdm5a). In addition, the ovarian damage caused by DEHP was also relieved after the overexpression of CEBPB, which suggested melatonin could improve primordial follicle formation progress via enhancing CEBPB expression in mice. Besides, the apoptosis of ovarian cells induced by DEHP also was diminished by melatonin. The study provides evidence of melatonin preventing the damage mediated by plasticizers on the reproductive system in females and CEBPB may serve as a downstream target factor of melatonin in the process.

Influence of cancer-directed surgery on the prognosis of liver metastases from gastric cancer.

There are controversial about the application of cancer-directed surgery (CDS) in patients with liver metastases from gastric cancer, with improved responses to chemotherapy and targeted treatments, the role of CDS in metastatic gastric cancer to the liver needs to be revisited. This study aimed to evaluate the effect of CDS on patients with liver metastases from gastric cancer. Data for patients with liver metastases from gastric cancer were extracted from the population-based Surveillance, Epidemiology, and End Results (SEER) database. A total of 958 individuals were enrolled, 285 in the CDS group and 673 in the non-cancer guided surgery (Non-CDS) group. Following propensity score matching (PSM) analysis at 1:1 in the two groups,285 were included in the survival analysis for each group. Kaplan-Meier values and Cox proportional risk models were used to estimate the effect of CDS on patients' prognoses. Compared with the Non-CDS group, the CDS group significantly prolonged the median overall survival from 4 months (95% confidence interval [CI] 3-5) to 11 months (95% CI 8-12), p value < 0.001. Overall survival (OS) at 1 year was higher in the CDS group than in the Non-CDS group, at 44% (95 CI 38-50) and 25% (95 CI 20-30), respectively. OS at 3 years was also higher in the CDS group than in the Non-CDS group, at 24% (95 CI 19-29) and 6% (95 CI 3-9), respectively. Multivariate analysis showed that Non-CDS (hazard ratio[HR] = 2.26, 95% CI 1.88-2.72, p value < 0.001) was an adverse independent prognostic factor for patients. This study concludes that CDS prolonged survival in patients with gastric cancer with liver metastases. Due to the lack of information on the quality of life, biomarkers, targeted therapies, and immunotherapy in the SEER database, the observed improved survival rates following CDS of hepatic metastasis from gastric cancer requires prospective studies that take these factors into account to properly address the survival advantages and impact on quality of life of such a method.

Aluminum hydroxide nanoparticle adjuvants can reduce the inflammatory response more efficiently in a mouse model of allergic asthma than traditional aluminum hydroxide adjuvants.

Traditional aluminum hydroxide is widely used as a vaccine adjuvant. Despite its favorable safety profile, it can cause an inflammatory response at the injection sites. However, multiple studies have shown that aluminum hydroxide nanoparticles have more potent adjuvant activity than their traditional aluminum hydroxide counterparts as antigen carriers; it has also been found that the local inflammation caused by aluminum hydroxide nanoparticle adjuvants is milder than that of other adjuvants. The aim of the present study was to compare the degree of inflammatory response between the aluminum hydroxide nanoparticle adjuvants and the traditional aluminum hydroxide adjuvants in the desensitization treatment of a mouse model of house dust mite (HDM)-induced allergic asthma. Mice were sensitized intraperitoneally with HDM. Subcutaneous desensitization was performed with PBS, traditional aluminum hydroxide adjuvants and aluminum hydroxide nanoparticle adjuvants. The mice were challenged and subsequently euthanized. The skin tissue at the local injection sites was assessed and specific indices were measured, such as the response of specific immunoglobulins, the airway hyper-responsiveness (AHR), and the inflammation in the bronchoalveolar lavage and lung tissues. Early hypersensitivity responses were suppressed in mice treated with subcutaneous immunotherapy (SCIT). Both traditional aluminum hydroxide-SCIT and aluminum hydroxide nanoparticle-SCIT could inhibit AHR. However, aluminum hydroxide nanoparticle-SCIT was able to significantly inhibit the secretion of eosinophils in the lung tissue and the production of type 2 cytokine Interleukin (IL)-5 in blood compared with the corresponding effects noted by traditional aluminum hydroxide adjuvants. Moreover, the aluminum hydroxide nanoparticle group reduced the inflammatory response at the local injection site. Collectively, the data indicated that allergen-specific immunotherapy using aluminum hydroxide nanoparticle adjuvants reduces lung and local inflammation compared with traditional aluminum hydroxide adjuvants.