BackgroundDespite advances in cardiac tissue engineering, generating constructs that simultaneously achieve vascularization and organized cardiomyocyte function remains a major challenge.MethodsIn this study, three-dimensional (3D) bioprinting was used to fabricate human umbilical vein endothelial cell (HUVEC)-laden alginate/gelatin constructs with defined architectures designed to mimic myocardial alignment. Constructs were cultured with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) under static conditions followed by short-term dynamic stimulation in a bioreactor. Cardiomyocytes - H9c2 cells, neonatal rat ventricular myocytes (NRVMs), or human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) - were subsequently seeded onto the constructs. Vascularization and the distribution of cells were assessed using immunofluorescence, and functional activity of cardiomyocytes was evaluated by calcium transient imaging.ResultsBioprinted constructs developed interconnected CD31-positive endothelial networks in response to growth factor supplementation and dynamic culture, whereas control constructs cultured without growth factors or bioreactor exposure showed limited vascular organization. Cardiomyocytes seeded onto vascularized constructs exhibited improved structural organization, including increased alignment and integration with endothelial networks. Functional assessment revealed more synchronized and rhythmic calcium transients compared to non-vascularized constructs.ConclusionThis study demonstrates that combining 3D bioprinting with controlled architectural design and endothelial network formation enhances cardiomyocyte organization and function. These findings highlight the critical role of vascular-like networks in improving the performance of engineered cardiac tissues.
The lack of pediatric indications and age-appropriate formulations in Canada has been a major concern for the pediatric community for decades. Although small patient populations and onerous approval processes may deter drug manufacturers from developing or marketing these drugs and formulations, the lack of adequate incentives may also contribute to the problem. In July, 2026, Canada issued a Ministerial Order allowing certain drugs to be approved by relying on reviews conducted by foreign regulatory agencies, with pediatric drugs selected as the first pilot category. Reviews of literature, media publications, guidance documents, government, particularly regulatory documents and product information were conducted to explore Canada’s historical record of pediatric approvals with comparison to US and EU. Problems associated with lack of pediatric medications in Canada were identified. The Ministerial Order of Reliance together with the guidance document were examined to determine whether the proposed reform will solve the pediatric medication crisis in Canada. The Reliance Order may help to alleviate some regulatory nuance and speed up approval times, however, is this sufficient to compel sponsors to submit with no mandatory requirements or added incentives under the current proposal. The submission fee and labour involved probably will outweigh commercial return in most cases, thus not an attractive option for sponsors, leading to unsuccessful outcomes. The manuscript attempts to identify gaps and provide recommendations to ensure the amended policy and new guidance will be enabling to achieve the desired outcomes.
BackgroundDemonstrating bioequivalence for locally acting inhaled products is challenging because systemic exposure may reflect both pulmonary absorption and gastrointestinal absorption of the swallowed fraction. Activated charcoal can suppress gastrointestinal uptake and may help interpret lung-derived exposure more directly.MethodsTwo open-label, randomized, single-dose, four-period crossover pharmacokinetic bioequivalence trials were conducted in healthy Chinese adults, one under non-block conditions and one under charcoal-block conditions. Thirty-six subjects were enrolled in each trial. In each period, subjects inhaled a single 1 mg dose of the test or reference budesonide inhalation suspension via a standardized jet nebulizer procedure, with a 5-day washout between periods. Plasma budesonide concentrations were measured for 15 h. The primary pharmacokinetic endpoints were Cmax, AUC0-t, and AUC0-inf, and bioequivalence was concluded if the 90% confidence intervals for the test/reference geometric mean ratios were within 80.00%–125.00%.ResultsUnder both non-block and charcoal-block conditions, the 90% confidence intervals for Cmax, AUC0-t, and AUC0-inf met the predefined bioequivalence criteria. In exploratory between-cohort comparisons based on subject-level arithmetic summaries, activated-charcoal blockade was associated with numerically lower AUC values, whereas Cmax remained similar; however, nominal exploratory P values for Cmax, AUC0-t, and AUC0-inf were all >0.05 and were not used for confirmatory inference. These findings are consistent with, but do not establish, a predominant pulmonary contribution to systemic exposure after nebulization. Both formulations were well tolerated, and no serious adverse events were reported.ConclusionThe test and reference budesonide inhalation suspension formulations were bioequivalent under both non-block and charcoal-block conditions. Exploratory between-cohort comparisons showed no statistically significant differences in Cmax, AUC0-t, or AUC0-inf based on nominal P values. The charcoal-related findings are consistent with, but do not establish, a predominant pulmonary contribution to systemic exposure after nebulization and should be interpreted cautiously because the conditions were evaluated in separate cohorts. Overall, the two studies provide supportive pharmacokinetic evidence for the evaluation of generic nebulized budesonide products.Trial RegistrationClinical Trial Registration: Drug Clinical Trial Registration and Information Publicity Platform of the National Medical Products Administration of China, CTR20200344 and CTR20201473 (http://www.chinadrugtrials.org.cn/); Chinese Clinical Trial Registry, ChiCTR2000035173 (https://www.chictr.org.cn/).
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ), a pathological hallmark implicated in disease onset and progression. Aβ undergoes self-assembly from monomers into soluble oligomers, protofibrils, insoluble fibrils, and extracellular plaques. Our previous studies have shown that Jowiseungchungtang, which consists of 14 medicinal herbs, inhibits Aβ aggregation and ameliorates Aβ-mediated pathology in AD models. However, the active small molecules underlying these effects remain unidentified. To identify small molecules from these 14 medicinal herbs, we constructed a library of 1,751 compounds and applied an integrated in silico and in vitro workflow. First, these 1,751 compounds were filtered based on drug-likeness and predicted blood-brain barrier permeability, yielding 566 candidates. Second, molecular docking of 566 selected compounds against Aβ conformers identified five candidates predicted to interact with aggregation-prone residues critical for Aβ aggregation and fibril stabilization. Third, Thioflavin T assays demonstrated that four compounds—1-monopalmitin, isobutyl octyl oxalate, pentadecanoic acid, and dimethyl azelate—significantly inhibited Aβ42 aggregation. Additionally, isobutyl octyl oxalate and pentadecanoic acid disaggregated preformed Aβ42 aggregates. Fourth, molecular dynamics simulations were performed to examine the short-timescale behavior of the candidate compounds with the Aβ17–42 dimer, showing transient ligand–Aβ interactions associated with structural rearrangements at the dimer interface. Pharmacokinetic predictions supported drug-likeness, showing blood-brain barrier permeability and systemic clearance. Collectively, these findings identify four Jowiseungchungtang (JWS)-derived candidate compounds with Aβ aggregation-inhibitory activity and provide a mechanistic and pharmacokinetic basis for further development of these compounds as potential therapeutic agents in AD.
Type 2 diabetes mellitus (T2DM) and obesity are closely interconnected but heterogeneous conditions in which treatment response, safety, body weight, glycemic control, and long-term clinical outcomes vary substantially between individuals. This narrative review evaluates emerging anti-obesity pharmacotherapy in patients with coexisting T2DM and obesity and examines the translational role of multi-omics in future precision treatment selection. Distinct from reviews focused primarily on obesity pharmacotherapy or omics-based disease stratification, the present review emphasizes the interface between contemporary drug mechanisms, T2DM-associated metabolic heterogeneity, candidate molecular signatures, and the level of evidence required for clinically actionable prescribing. We summarize evidence for approved and investigational oral incretin therapies, dual and triple receptor agonists, amylin-based strategies, established antidiabetic drugs, and adjunctive approaches targeting body composition. Throughout the review, we distinguish established clinical evidence from mechanistic rationale, candidate biomarkers, exploratory associations, and hypothetical future precision applications. We also separate metabolic efficacy endpoints, such as body weight and HbA1c, from intermediate cardiometabolic risk markers and from cardiovascular or kidney outcomes demonstrated in dedicated outcome trials. At present, no genomic, metabolomic, lipidomic, proteomic, microbiome, or integrated multi-omics signature has been clinically validated to select a specific anti-obesity medication for patients with T2DM and obesity. Major unresolved issues include the need for prospective biomarker validation, direct comparative trials, standardized assays, externally validated and calibrated prediction models, preservation of skeletal muscle health and physical function, long-term safety, treatment durability, affordability, and equitable implementation. Multi-omics should therefore be viewed as an investigational framework for generating and testing precision-treatment hypotheses rather than as a basis for routine prescribing.
