Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Lung injuries induced by ozone exposure in female mice: Potential roles of the gut and lung microbes.

Ozone (O3) is one of the most harmful pollutants affecting health. However, the potential effects of O3 exposure on microbes in the gut-lung axis related to lung injuries remain elusive. In this study, female mice were exposed to 0-, 0.5- and 1-ppm O3 for 28 days, followed by routine blood tests, lung function tests and histopathological examination of the colon, nasal cavity and lung. Mouse faeces and lungs were collected for 16s rRNA sequencing to assess the overall microbiological profile and screen for key differential enriched microbes (DEMs). The key DEMs in faecal samples were Butyricimonas, Rikenellaceae RC9 and Escherichia-Shigella, whereas those in lung samples were DNF00809, Fluviicola, Bryobacter, Family XII AD3011 group, Sharpea, MND1 and unclassified Phycisphaeraceae. After a search in microbe-disease databases, these key DEMs were found to be associated with lung diseases such as lung neoplasms, cystic fibrosis, pneumonia, chronic obstructive pulmonary disease, respiratory distress syndrome and bronchiectasis. Subsequently, we used transcriptomic data from Gene Expression Omnibus (GEO) with exposure conditions similar to those in this study to cross-reference with Comparative Toxicogenomic Database (CTD). Il-6 and Ccl2 were identified as the key causative genes and were validated. The findings of this study suggest that exposure to O3 leads to significant changes in the microbial composition of the gut and lungs. These changes are associated with increased levels of inflammatory factors in the lungs and impaired lung function, resulting in an increased risk of lung disease. Altogether, this study provides novel insights into the role of microbes present in the gut-lung axis in O3 exposure-induced lung injury.

Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives.

Reproductive disorders are considered a global health problem influenced by physiological, genetic, environmental, and lifestyle factors. The increased exposure to bisphenols, a chemical used in large quantities for the production of polycarbonate plastics, has raised concerns regarding health risks in humans, particularly their endocrine-disrupting effects on female reproductive health. To provide a basis for future research on environmental interference and reproductive health, we reviewed relevant studies on the exposure patterns and levels of bisphenols in environmental matrices and humans (including susceptible populations such as pregnant women and children). In addition, we focused on in vivo, in vitro, and epidemiological studies evaluating the effects of bisphenols on the female reproductive system (the uterus, ovaries, fallopian tubes, and vagina). The results indicate that bisphenols cause structural and functional damage to the female reproductive system by interfering with hormones; activating receptors; inducing oxidative stress, DNA damage, and carcinogenesis; and triggering epigenetic changes, with the damaging effects being intergenerational. Epidemiological studies support the association between bisphenols and diseases such as cancer of the female reproductive system, reproductive dysfunction, and miscarriage, which may negatively affect the establishment and maintenance of pregnancy. Altogether, this review provides a reference for assessing the adverse effects of bisphenols on female reproductive health.

Bisphenol B and bisphenol AF exposure enhances uterine diseases risks in mouse.

Bisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPB and BPAF exposure need to be further elucidated. The study aimed to explore whether BPB or BPAF exposure will induce adverse outcomes in uterus. Female CD-1 mice were continuously exposed to BPB or BPAF for 14 and 28 days. Morphological examination showed that BPB or BPAF exposure caused endometrial contraction, decreased epithelial height, and increased number of glands. Bioinformatics analysis indicated that both BPB and BPAF disturbed the immune comprehensive landscape of the uterus. In addition, survival and prognosis analysis of hub genes and tumor immune infiltration evaluation were performed. Finally, the expression of hub genes was verified by quantitative real-time PCR (qPCR). Disease prediction found that eight of the BPB and BPAF co-response genes, which participated in the immune invasion of the tumor microenvironment, were associated with uterine corpus endometrial carcinoma (UCEC). Importantly, the gene expression levels of Srd5a1 after 28-day BPB and BPAF exposure were 7.28- and 25.24-fold higher than those of the corresponding control group, respectively, which was consistent with the expression trend of UCEC patients, and its high expression was significantly related to the poor prognosis of patients (p = 0.003). This indicated that Srd5a1 could be a valuable signal of uterus abnormalities caused by BPA analogs exposure. Our study revealed the key molecular targets and mechanisms of BPB or BPAF exposure induced uterine injury at the transcriptional level, providing a perspective for evaluating the safety of BPA substitutes.

Identification of risk for ovarian disease enhanced by BPB or BPAF exposure.

The ban on bisphenol A (BPA) has led to a rapid increase in the use of BPA analogs, and they are increasingly being detected in the natural environment and biological organisms. Studies have pointed out that BPA analogs can lead to adverse health outcomes. However, their interference with ovarian tissue has not been fully elucidated. In this study, seven- to eight-week-old CD-1 mice were exposed to corn oil containing 300 µg/kg/day bisphenol B (BPB) or bisphenol AF (BPAF) through oral gavage, and ovarian tissues were collected at 14 and 28 days of exposure. Ovarian toxicity was evaluated by the ovarian index, ovarian area, and follicle number. mRNA-seq was used to identify differentially expressed genes (DEGs) and infer the association of DEGs with ovarian diseases. BPB or BPAF exposure induced morphological changes in ovarian tissue in CD-1 mice. In addition, Gene Ontology (GO) analysis revealed disturbances in biological processes (BP) associated with steroid biosynthetic process (GO:0006694) and cellular calcium ion homeostasis (GO:0006874). Subsequently, regulatory networks of BPA analogs (BPB or BPAF)-DEGs-ovarian diseases were constructed. Importantly, the expression levels of DEGs and transcription factors (TFs) associated with ovarian disease were altered. BPB or BPAF exposure causes damage to ovarian morphology through the synergistic effects of multiple biological processes and may be associated with altered mRNA expression profiles as a risk factor for ovarian diseases.

Exploration of the damage and mechanisms of BPS exposure on the uterus and ovary of adult female mice.

Bisphenol S (BPS) has been followed with interest for its endocrine disrupting effects, but exploration on the reproductive system of adult females is lack of deep investigation. In the present study, adult female CD-1 mice were treated with BPS for 28 days at 300 µg/kg/day. After that, uteruses and ovaries were harvested for histopathological examination, RNA-seq analysis, and diseases risk prediction. Hematoxylin-eosin (H&E) staining results showed significant histological alterations in the uterus and ovary of the BPS-exposed mice. Bioinformatics analysis of the RNA-seq screened a certain number of differentially expressed genes (DEGs) in both uterus and ovary between BPS group and their corresponding vehicle control groups (Veh), respectively. Functional enrichment analysis of DEGs found that hormone metabolism and immunoinflammatory related pathways were enriched. Disease risk evaluation of the hub genes was performed and the results indicated that diseases associated with uterus and ovary were mainly related to tumors and cancers. Further pan cancer and ovarian cancer survival analysis based on human diseases database pointed out, Foxa1, Gata3, S100a8 and Shh for uterus, Itgam, Dhcr7, Fdps, Hmgcr, Hsd11b1, Hsd3b1, Ptges, F3, Fn1, Ptger4 and Srd5a1 for ovary were significant correlation with cancer. The findings suggest that BPS causes some histopathological changes, alters the expressions of hub genes, enhances uterine and ovarian tumors or even cancer risks.

Fabrication of bilayer tablets using hot melt extrusion-based dual-nozzle fused deposition modeling 3D printing.

The objective of this study was to fabricate bilayer tablets using hot-melt extrusion (HME)-based dual-nozzle fused deposition modeling (FDM) three-dimensional (3D) printing techniques. Acetaminophen (APAP) and caffeine citrate (CC) were used as the model drugs. Five bilayer tablets with different formulations were developed and two different structures were printed for each formulation. Three-point bending, Hooke's law, and resistance and stiffness tests were conducted to determine the mechanical properties of the filaments. A novel method, 3D printed tablet retention rate, was developed and used for the first time to compare the printing quality of different filaments. The 3D printed tablets were evaluated to derive the drug release rates using a USP-II dissolution apparatus. HPMC HME 15LV and HPMCAS-LG were identified as good printing materials; however, HPMC HME 100LV was not suitable for printing under frequent nozzle switching conditions. Although mechanical characterization tests can be used to determine whether filaments can be printed, they cannot specifically distinguish the quality of printing between the filaments. Overall, this study revealed the successful fabrication of bilayer tablets via HME paired with dual-nozzle FDM 3D printing.

Prediction and Construction of Drug-Polymer Binary System Thermodynamic Phase Diagram in Amorphous Solid Dispersions (ASDs).

Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory-Huggins (F-H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔGmix). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.

Oral drug delivery systems using core-shell structure additive manufacturing technologies: a proof-of-concept study.

OBJECTIVES: The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core-shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment. METHODS: Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets. KEY FINDINGS: Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release. CONCLUSIONS: The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations.

Development of a quantitative method to evaluate the printability of filaments for fused deposition modeling 3D printing.

Lack of a conventional quantitative characterization method for filament printability has been recognized as a critical barrier to fused deposition modeling (FDM) 3D printing application. In this study, a small molecule drug, indomethacin, was utilized as a model compound. Polymers with various solubility were mixed with model drug and extruded into filaments using hot melt extrusion method. Thirty-two filaments with or without indomethacin were evaluated by texture analyzer to study the correlation between mechanical properties and the printability. Three different texture analysis methods were utilized and compared, and a parameter "toughness" calculated by stiffness test was identified to quantitatively describe the printability of filaments in the FDM 3D printer. The toughness threshold value of printable filament was defined as a process window of certain FDM printing. This study provides a quantitative way to evaluate and predict filament printability, and it has great potential to be applied to FDM filament development and quality control in the pharmaceutical industry.

A Novel Acetaminophen Soft-Chew Formulation Produced via Hot-Melt Extrusion with In-line Near-Infrared Monitoring as a Process Analytical Technology Tool.

Patients who suffer from dysphagia have difficulty in swallowing hard tablets and capsules; hence, gelatin-based soft-chew dosages are used as an alternative and novel drug delivery approach to overcome this problem. However, the conventional method of producing gelatin-based soft-chew dosages has many potential issues. The objective of this study was to use glycerol and the hot-melt extrusion technique to address potential issues and optimize the formulation. Gelatin, acetaminophen, saccharin, xylitol, and sodium chloride and six different ratios of water and glycerol were used in the seven formulations. Extrusion process temperature of formulations 1-6 and formulation 7 were 90°C and 140°C, respectively. Near-infrared spectra were collected during extrusion to monitor quality consistency. Scanning electron microscopic images of the cross-section of the soft-chew dosages were recorded. Differential scanning calorimetry (DSC) was used to characterize the crystal states of each formulation. Texture profile analysis was used to evaluate the physical properties of the tablets. In vitro drug release characteristics were studied. A 45-day stability study was carried out to evaluate the stability of each formulation. Near-infrared spectra showed that formulations 1-6 were uniform while formulation 7 was not. From the DSC results, formulations 1 and 2 showed crystallinity of acetaminophen. Formulation 5 displayed the desired physical and chemical stability in texture profile analysis and in the in vitro drug release studies. By using glycerol and hot-melt extrusion, the potential issues of conventional methods were successfully addressed.

Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization.

Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.