Prenatal prednisone exposure impacts liver development and function in fetal mice and its characteristics.

Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress the cell proliferation, inhibit hepatocyte differentiation and promote cholangiocyte differentiation in fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid ß-oxidation and hematopoiesis in fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage- and sex-differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-10), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway.

Epigenetic programming mediates abnormal gut microbiota and disease susceptibility in offspring with prenatal dexamethasone exposure.

Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the relationship with disease susceptibility remains unclear. In this study, we find sex-differential changes in the gut microbiota of 6-month-old infants with prenatal dexamethasone therapy (PDT) that persisted in female infants up to 2.5 years of age with altered bile acid metabolism. PDE female offspring rats show abnormal colonization and composition of gut microbiota and increased susceptibility to cholestatic liver injury. The aberrant gut microbiota colonization in the PDE offspring can be attributed to the inhibited Muc2 expression caused by decreased CDX2 expression before and after birth. Integrating animal and cell experiments, we further confirm that dexamethasone could inhibit Muc2 expression by activating GR/HDAC11 signaling and regulating CDX2 epigenetic modification. This study interprets abnormal gut microbiota and disease susceptibility in PDT offspring from intrauterine intestinal dysplasia.

Change in function and homeostasis of HPA axis: The role of vitamin family.

With the improvement of living quality, people pay more and more attention to vitamin supplements. The vitamins in the daily diet can meet the needs of the body. Whether additional vitamin supplementation is necessary still needs to be further explored. Many studies have reported that vitamin deficiency and excessive vitamin supplementation could lead to abnormal development in the body or increase the risk of diseases. Here, we summarize the abnormal levels of vitamins can cause the homeostasis imbalance of hypothalamus-pituitary-adrenal (HPA) axis by affecting its development and function. It can lead to abnormal synthesis and secretion of glucocorticoid in the body, which mediates the occurrence and development of metabolic diseases and psychoneurotic diseases. In addition, vitamin has a strong antioxidant effect, which can eliminate oxygen free radicals. Thereby, vitamins can alter HPA axis function and homeostasis maintenance by combating oxidative stress. This review provides a theoretical basis for clarifying the role of abnormal levels of vitamin in the occurrence and development of multiple diseases and its intervention strategy, and also provides reference value and guiding significance for rational use of vitamins.

Public knowledge and willingness in the use of public access defibrillation of Hubei Province in China: A cross-sectional study.

To understand the current status of public knowledge of automated external defibrillator (AED) and their willingness to use public AED in Hubei Province, along with the influencing factors. A self-designed questionnaire was used for convenience sampling of the public in Hubei Province. The questionnaire consists of three parts: basic information, AED knowledge questions, and willingness to use public AED and influencing factors. Data was collected between May 2022 and March 2023. A total of 1561 valid questionnaires were collected from 1602 distributed. In the study conducted in Hubei Province, it was found that 875 respondents (56.05%) had knowledge of automated external defibrillator, and they achieved an average score of 39.27 ± 29.17. The pass rate for the survey was 28.11%. Several factors were identified as significant influencing factors, including gender, age, education level, occupation related to medicine, residential location in the past three years, family members with cardiovascular disease, marital status, residential population density, whether there are family members over 65 years old, and participation in AED-related training (P < .05).Furthermore, 692 respondents (72.99%) expressed their willingness to cardiopulmonary resuscitation for someone experiencing cardiac arrest. On the other hand, 686 respondents (43.95%) had no knowledge of AED. Among those who were not willing to perform defibrillation, the highest percentages cited "fear of incorrect use" (129, 31.2%) and "fear of harming the patient" (121, 29.3%) as their reasons. The study also found statistically significant differences in the willingness to use public AED based on participation in training, education level, residential location, family members with cardiovascular disease, population density, and the presence of elderly family members aged 65 or over (P < .05). In conclusion, the study highlights the general lack of public knowledge regarding AED in Hubei Province. However, there is a strong willingness among respondents to provide help during cardiac arrest situations. To improve the chances of survival for cardiac arrest patients, it is crucial to strengthen public AED training programs.

Transcriptome analysis reveals the neuroactive receptor genes response to Streptococcus agalactiae infection in tilapia, Oreochromis niloticus.

The detailed crosstalk between the neuroendocrine and immune systems in Oreochromis niloticus, an economically important fish, in response to pathogenic infections, remains unclear. This study revealed the head kidney transcriptional profiles of O. niloticus upon infections with Streptococcus agalactiae, a prevalent pathogen known to cause severe meningitis. Twelve cDNA libraries of O. niloticus head kidney, representing four treatment time points (0, 6, 24, and 48 h), were constructed and a total of 2,528 differentially expressed genes were identified based on pairwise comparisons. KEGG pathway analysis revealed a significant enrichment of the 'neuroactive ligand-receptor interaction' pathway (ko04080), with 13 genes exhibiting differential expression during S. agalactiae infection. Among these, six neuroactive receptor genes (lepr, nr3c1, ptger4, thrb, tspo, and ß2-ar) were selected, cloned, and characterized. Although these genes are ubiquitously expressed, and in head kidney leukocytes, their expression was mainly observed in T cells, Mo/Mφ, and NCCs, which are characterized by antimicrobial responses. Furthermore, we examined the response patterns of these six neuroactive receptor genes to gram-positive (S. agalactiae) and gram-negative (Aeromonas hydrophila) bacteria in four different tissues. Notably, lepr, ptger4, tspo, and ß2-ar were upregulated in all selected tissues in response to S. agalactiae and A. hydrophila infections. However, nr3c1 and thrb were downregulated in response to S. agalactiae infection in the head kidney and spleen, whereas nr3c1 was upregulated, and thrb was unresponsive to A. hydrophila infection. Our findings provide a theoretical foundation for understanding new links between the neuroendocrine and immune systems during bacterial infection in teleost fish.

C-H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT-2 Inhibitors.

C-Glycosides are critical motifs embedded in many bioactive natural products. The inert C-glycosides are privileged structures for developing therapeutic agents owing to their high chemical and metabolic stability. Despite the comprehensive strategies and tactics established in the past few decades, highly efficient C-glycoside syntheses via C-C coupling with excellent regio-, chemo-, and stereoselectivity are still needed. Here, we report the efficient Pd-catalyzed glycosylation of C-H bonds promoted by weak coordination with native carboxylic acids without external directing groups to install various glycals to the structurally diverse aglycon parts. Mechanistic evidence points to the participation of a glycal radical donor in the C-H coupling reaction. The method has been applied to a wide range of substrates (over 60 examples), including many marketed drug molecules. Natural product- or drug-like scaffolds with compelling bioactivities have been constructed using a late-stage diversification strategy. Remarkably, a new potent sodium-glucose cotransporter-2 inhibitor with antidiabetic potential has been discovered, and the pharmacokinetic/pharmacodynamic profiles of drug molecules have been changed using our C-H glycosylation approach. The method developed here provides a powerful tool for efficiently synthesizing C-glycosides to facilitate drug discovery.

Pathological characteristics of breast nodules after large-volume fat grafting for breast augmentation.

BACKGROUND: The complications of large-volume fat grafting (LVFG) for breast augmentation remain unpredictable and include palpable breast nodules, oil cysts, and calcifications. AIMS: This study was aimed to provide an optimal treatment option for breast nodules after LVFG and evaluate their pathological characteristics. PATIENTS/METHODS: We effectively performed complete resection of breast nodules in 29 patients after LVFG using a minimal skin incision with the vacuum-assisted breast biopsy (VABB) system under ultrasound guidance. And we further carried on histologic examination of excised nodules and evaluated their pathological characteristics. RESULTS: The breast nodules were excised thoroughly with cosmetic effect satisfactorily. Interestingly, subsequent histologic examination showed that type I and VI collagens were strongly expressed in the fibrotic area and type IV collagen were positively expressed around the blood vessel. Furthermore, we found that the type VI collagen+ area appeared around mac2+ macrophages and α-SMA+ myofibroblasts. CONCLUSIONS: The VABB system may be the optimal treatment option for breast nodules after LVFG. And type VI collagens may serve as a biomarker of grafted adipose tissue fibrosis. The relationship between macrophages, fibroblasts, and collagen formation may be therapeutic targets for regulating fibrosis.

Development of Matrix Metalloproteinases-Mediated Extracellular Matrix Remodeling in Regenerative Medicine: A Mini Review.

Extracellular matrix (ECM) components confer biomechanical properties, maintain cell phenotype and mediate tissue homeostasis. ECM remodeling is complex and plays a key role in both physiological and pathological processes. Matrix metalloproteinases (MMPs) are a group of enzymes responsible for ECM degradation and have been accepted as a key regulator in ECM remodeling. In this mini-review, we summarize MMPs categories, functions and the targeted substrates. We then discuss current understanding of the role of MMPs-mediated events, including inflammation reaction, angiogenesis, cellular activities, etc., in ECM remodeling in the context of regenerative medicine.

Prenatal exposure to corn oil, CMC-Na or DMSO affects physical development and multi-organ functions in fetal mice.

Corn oil, sodium carboxymethyl cellulose (CMC-Na), and dimethyl sulfoxide (DMSO) are widely used as solvents or suspensions in animal experiments, but the effects of prenatal exposure to them on fetal development have not been reported. In this study, Kunming mice were given a conventional dose of corn oil (9.2 g/kg·d), CMC-Na (0.05 g/kg·d) or DMSO (0.088 g/kg·d) during gestation days 10-18, and the pregnancy outcome, fetal physical development, serum phenotype, and multi-organ function changes were observed. The results showed that corn oil decreased serum triglyceride level in males but increased their serum testosterone and CORT levels, and affected female placenta and female/male multi-organ functions (mainly bone, liver, kidney). CMC-Na increased female/male body lengths and tail lengths, decreased serum glucose and total cholesterol levels in males as well as increased their serum LDL-C/HDL-C ratio and testosterone level, decreased female serum bile acid level, and affected male/female placenta and multi-organ functions (mainly bone, liver, hippocampus). DMSO decreased male body weight and serum glucose level, decreased male/female serum bile acid levels, and affected male/female placenta and multi-organs functions (mainly bone, hippocampus, adrenal gland). In conclusion, prenatal exposure to a conventional dose of corn oil, CMC-Na or DMSO could affect fetal physical development and multi-organ functions, and has the characteristics of "multi-pathway, multi-organ and multi-target". This study provides the experimental basis for the rational selection of solvents or suspensions in pharmacology and toxicology studies.

Ginsenoside Rc: A potential intervention agent for metabolic syndrome.

Ginsenoside Rc, a dammarane-type tetracyclic triterpenoid saponin primarily derived from Panax ginseng, has garnered significant attention due to its diverse pharmacological properties. This review outlined the sources, putative biosynthetic pathways, extraction, and quantification techniques, as well as the pharmacokinetic properties of ginsenoside Rc. Furthermore, this study explored the pharmacological effects of ginsenoside Rc against metabolic syndrome (MetS) across various phenotypes including obesity, diabetes, atherosclerosis, non-alcoholic fatty liver disease, and osteoarthritis. It also highlighted the impact of ginsenoside Rc on multiple associated signaling molecules. In conclusion, the anti-MetS effect of ginsenoside Rc is characterized by its influence on multiple organs, multiple targets, and multiple ways. Although clinical investigations regarding the effects of ginsenoside Rc on MetS are limited, its proven safety and tolerability suggest its potential as an effective treatment option.

Development of an Ingestible Expandable Capsule for Weight Loss.

Obesity has grown to epidemic proportions with 2.1 billion people being overweight worldwide. A food-grade expandable capsule named EndoXpand for the treatment of overweight people was designed and developed in this study. EndoXpand consists of an inner expandable material (core), an embracing membrane, and a gelatin capsule shell. It is designed to occupy volume in the stomach and reduce hunger sensation. The occupied volume is changeable over time, dependent on the number of ingested capsules and their degradation time. This will avoid gastric accommodation to constant volume devices as seen in the use of intragastric balloons. Several materials were tested. Collagen casing was selected as the membrane and corn silk was used to tie the membrane. Dried black fungus (Auricularia auricula) was the biological material that expanded most. However, synthesized cellulose-based hydrogel expanded more and was chosen as the optimal expandable core material. The hydrogel-based EndoXpand expanded 72 times after soaking in an acidic environment for 80 min. The corn silk ligations weakened and broke after 3 h. This resulted in release of the expanded material that was designed to easily pass the pylorus and travel down the intestine for digestion or excretion. In conclusion, this study provides design and in vitro proof-of-technology data for a potential groundbreaking approach. Further studies are needed in animal models and human phase I studies.

Inflammation-mediated matrix remodeling of extracellular matrix-mimicking biomaterials in tissue engineering and regenerative medicine.

Extracellular matrix (ECM)-mimicking biomaterials are considered effective tissue-engineered scaffolds for regenerative medicine because of their biocompatibility, biodegradability, and bioactivity. ECM-mimicking biomaterials preserve natural microstructures and matrix-related bioactive components and undergo continuous matrix remodeling upon transplantation. The interaction between host immune cells and transplanted ECM-mimicking biomaterials has attracted considerable attention in recent years. Transplantation of biomaterials may initiate injuries and early pro-inflammation reactions characterized by infiltration of neutrophils and M1 macrophages. Pro-inflammation reactions may lead to degradation of the transplanted biomaterial and drive the matrix into a fetal-like state. ECM degradation leads to the release of matrix-related bioactive components that act as signals for cell migration, proliferation, and differentiation. In late stages, pro-inflammatory cells fade away, and anti-inflammatory cells emerge, which involves macrophage polarization to the M2 phenotype and leukocyte activation to T helper 2 (Th2) cells. These anti-inflammatory cells interact with each other to facilitate matrix deposition and tissue reconstruction. Deposited ECM molecules serve as vital components of the mature tissue and influence tissue homeostasis. However, dysregulation of matrix remodeling results in several pathological conditions, such as aggressive inflammation, difficult healing, and non-functional fibrosis. In this review, we summarize the characteristics of inflammatory responses in matrix remodeling after transplantation of ECM-mimicking biomaterials. Additionally, we discuss the intrinsic linkages between matrix remodeling and tissue regeneration. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM)-mimicking biomaterials are effectively used as scaffolds in tissue engineering and regenerative medicine. However, dysregulation of matrix remodeling can cause various pathological conditions. Here, the review describes the characteristics of inflammatory responses in matrix remodeling after transplantation of ECM-mimicking biomaterials. Additionally, we discuss the intrinsic linkages between matrix remodeling and tissue regeneration. We believe that understanding host immune responses to matrix remodeling of transplanted biomaterials is important for directing effective tissue regeneration of ECM-mimicking biomaterials. Considering the close relationship between immune response and matrix remodeling results, we highlight the need for studies of the effects of clinical characteristics on matrix remodeling of transplanted biomaterials.

Biomimetic Total Synthesis and the Biological Evaluation of Natural Product (-)-Fargesone A as a Novel FXR Agonist.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays an important role in maintaining or reversing metabolic homeostasis during the development of liver diseases. However, developing FXR modulators to intervene in FXR-related diseases is still an unmet clinical need. Therefore, it is significant to develop novel small-molecule agonists for drug discovery targeting FXR. Through a high-throughput chemical screen and follow-up biological validations, we first identified the natural product Fargesone A (FA) as a potent and selective FXR agonist. The limited, variable supply of FA from natural product isolation, however, has impeded its biological exploration and potential drug development. Accordingly, we have developed a biomimetic and scalable total synthesis of FA in nine steps that provides a solution to the supply of FA. Enabled by chemical synthesis, the in vivo efficacy of FA has been further investigated. The results showed that FA alleviates hepatocyte lipid accumulation and cell death in an FXR-dependent manner. Moreover, treatment of bile duct ligation (BDL)-induced liver disorder with FA ameliorates pathological features in mice. Therefore, our work lays the foundation to develop new small-molecule FXR agonists as a potential therapy for liver diseases.

Pilot-scale evaluation of partial denitrification/anammox on nitrogen removal from low COD/N real sewage based on a modified process.

The nitrogen removal performance of a pilot-scale biosystem was significantly improved via partial denitrification/anammox (PD/A) in real sewage with low COD/N ratio. The modified pilot plant was designed as an anaerobic/anoxic/oxic (AAO) reactor combined with a biological aerated filter. The inoculation of biocarriers into anaerobic and anoxic zones enhanced anammox and the nitrogen removal performance. Despite a COD/N ratio of 3.1, effluent total inorganic nitrogen decreased from 17.1 to 9.8 mg N/L. The anoxic unit developed as the PD/A hotspot, which was associated with the enrichment of Ca. Brocadia (2.00%) and partial denitrification functional groups (OLB14, 13.50%; Thauera, 5.45%) in the anoxic-carrier biofilms and contributed 34.1% towards total nitrogen removal. Besides improving the PD/A process, enhanced denitrifying dephosphatation was simultaneously realized, suggesting that the integration of PD/A into this modified system is a promising approach to enhance nutrient removal of low COD/N wastewater.

In situ enrichment of anammox bacteria in anoxic biofilms are possible due to the stable and long-term accumulation of nitrite during denitrification.

In situ enrichment of anammox bacteria in anoxic biofilms has been observed, but the specific conditions for anammox competition with denitrification for nitrite are not yet fully understood. Therefore, an anoxic sequencing batch biofilm reactor (SBBR) was used to investigate nitrite production during denitrification. In each SBBR cycle, with nearly 80% of nitrate reduced in 3 h, over 9.7 mg/L nitrite was gradually accumulated and maintained for a long time, despite temperatures gradually decreasing from 32 to 5 â„ƒ. The long-term existence of nitrite was due to the low biofilm nitrite reduction rate (1.2 mgN gVSS-1 h-1), which was about 10-fold less than the nitrate reduction rate. Accordingly, nitrite reduction via denitrifiers was continuously suppressed, which was favorable for nitrite reduction through the anammox pathway. Indeed, anammox bacteria were successfully enriched here (Candidatus_Brocadia, 0.1%). This study confirms the potential of anoxic biofilm in enriching anammox bacteria and provides insight into understanding.

Simultaneous methanethiol and dimethyl sulfide removal in a single-stage biotrickling filter packed with polyurethane foam: Performance, parameters and microbial community analysis.

The bio-treatment of methanethiol (MT) and dimethyl sulfide (DMS), the most common sulfur compounds in odorous gas, is difficult due to the inhibition of DMS degradation by MT. This article investigated the treatment of MT and DMS odorous gas using a single-stage biotrickling filter (BTF) packed with polyurethane foam cubes that were inoculated with activated sludge from a sewage treatment plant operating an anaerobic/aerobic/oxic (AAO) process. The BTF system lasted for 161 days (with 9 days to startup) under an empty gas residence time of 39 s. The elimination capacities for MT and DMS were 85.2 g/m3/h (removal efficiency = 96.6%) and 6.4 g/m3/h (removal efficiency = 95.0%), respectively, and the maximal elimination capacities of MT and DMS were 119.7 g/m3/h and 7.3 g/m3/h, respectively. The optimal parameters were as follows: empty bed retention time, 39 s; pH, 6.1; recirculation medium flow rate, ≥1.2 m3/m2/h; temperature, 29-36 °C; and SO42- concentration, < 2.0 g-SO42-/L. Microbial community analysis revealed that spatial differentiation between MT-degrading bacteria and DMS-degrading bacteria enable the single-stage BTF can simultaneously remove MT and DMS. The activated sludge of AAO process can be used as the inoculation sludge to treating MT and DMS gas, which provides an important reference for the industrial application of treating odorous gas containing MT and DMS.

Biomimetic Synthesis of Rhytidenone†A and Mode of Action of Cytotoxic Rhytidenone†F.

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas-dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small-molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.

[Removal of Hydrogen Sulfide Produced in a Municipal WWTP Using a Biotrickling Filter with Polypropylene Rings as the Packing Material and Microbial Community Analysis].

Under transient conditions, a biotrickling filter was developed to treat gaseous H2S produced from the fine-grid reservoir of a municipal wastewater treatment plant (WWTP) with AAO excess sludge as the inoculum and polypropylene rings as the packing material. The start-up process and steady-state operation of the biotrickling filter were studied. With an empty bed retention time of 14 s, an ambient temperature of 7.8-32.5℃, and an inlet concentration of 2.02-319.19 mg·m-3, an average removal efficiency of 91.8% was achieved with a maximum H2S elimination capacity of 78.37 g·(m3·h)-1. Over a 247-day period, the pressure drop across the biotrickling filter was maintained at 96 Pa·m-1. Microbial analysis using high-throughput sequencing technology showed a variation in the microbial community during the experiment; the Shannon index dropped from 4.99 to 3.75, and the functional genera Pseudomonas and Thiobacillus were identified as good performers in the biotrickling filter system. These results indicate that the application of AAO excess sludge as an inoculum for biotrickling filters is feasible for effective H2S removal. A steady pressure drop was achieved using polypropylene rings as the packing material. The diversity of the microbial community showed a downward trend when exposed to H2S, but the elimination capacity could be increased.