Engineering three-dimensional (3D) sensible tissue constructs, along with the complex microarchitecture wiring of the sensory nervous system, has been an ongoing challenge in the tissue engineering field. By combining 3D bioprinting and human pluripotent stem cell (hPSC) technologies, sensible tissue constructs could be engineered in a rapid, precise, and controllable manner to replicate 3D microarchitectures and mechanosensory functionalities of the native sensory tissue (e.g. response to external stimuli). Here, we introduce a biofabrication approach to create complex 3D microarchitecture wirings. We develop an hPSC-sensory neuron (SN) laden bioink using highly purified and functional SN populations to 3D bioprint microarchitecture wirings that demonstrate responsiveness to warm/cold sense-inducing chemicals and mechanical stress. Specifically, we tailor a conventional differentiation strategy to our purification method by utilizing p75 cell surface marker and DAPT treatment along with neuronal growth factors in order to selectively differentiate neural crest cells into SNs. To create spatial resolution in 3D architectures and grow SNs in custom patterns and directions, an induced pluripotent stem cell (iPSC)-SN-laden gelatin bioink was printed on laminin-coated substrates using extrusion-based bioprinting technique. Then the printed constructs were covered with a collagen matrix that guided SNs growing in the printed micropattern. Using a sacrificial bioprinting technique, the iPSC-SNs were seeded into the hollow microchannels created by sacrificial gelatin ink printed in the gelatin methacryloyl supporting bath, thereby demonstrating controllability over axon guidance in curved lines up to several tens of centimeters in length on 2D substrates and in straight microchannels in 3D matrices. Therefore, this biofabrication approach could be amenable to incorporate sensible SN networks into the engineered skin equivalents, regenerative skin implants, and augmented somatosensory neuro-prosthetics that have the potential to regenerate sensible functions by connecting host neuron systems in injured areas.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic condition with significant morbidity and mortality, largely due to its vascular complications. The emergence of novel pharmacological agents, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), has revolutionized T2DM management by addressing glycemic control and comorbidities such as cardiovascular and renal diseases. Traditionally, GLP-1RAs require subcutaneous injection, presenting challenges in patient adherence and limiting combination therapy options. Recent advancements have introduced orally available small-molecule GLP-1RAs, which retain the physiological benefits of peptide-based GLP-1RAs, such as promoting insulin secretion, reducing appetite, and improving weight loss. These small molecules offer enhanced tissue permeability, extended half-lives, and the potential for fixed-dose combinations, addressing limitations of injectable formulations. This review explores the preclinical and clinical progress of small-molecule GLP-1RAs, highlighting their potential to redefine diabetes care by improving convenience, adherence, and accessibility for patients.

As temperatures continue to modify due to weather changes, more regions are being exposed to extreme heat and cold. Physiological distress due to low and high temperatures can affect the heart, blood vessels, liver, and especially, the kidneys. Dehydration causes impaired cell function and heat itself triggers cellular stress. The decline in circulating plasma volume by sweat, which stresses the renal and cardiovascular systems, has been related to some molecules that are crucial players in preventing or provoking cellular damage. Hypovolemia and blood redistribution to cutaneous blood vessels reduce perfusion to the kidney triggering the activation of the renin–angiotensin–aldosterone system. In this review, we expose a deeper understanding of the modulation of molecules that interact with other proteins in humans to provide significant findings in the context of extreme heat and cold environments and renal damage reversal. We focus on the molecular changes exerted by temperature and dehydration in the renal system as both parameters are heavily implicated by weather change (e.g., vasopressin-induced fructose uptake, fructogenesis, and hypertension). We also discuss the compensatory mechanisms activated under extreme temperatures that can exert further kidney injury. To finalize, we place special emphasis on the renal mechanisms of protection against temperature extremes, focusing on two important protein groups: heat shock proteins and sirtuins.

Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-Akt-eNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels with increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.

Recent cardiovascular outcome trials (CVOTs) have reshaped the therapeutic landscape of type 2 diabetes mellitus (T2DM), revealing that certain glucose-lowering agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), offer substantial cardiovascular benefits beyond glycemic control. Injectable GLP-1RAs, such as semaglutide and liraglutide, have been shown to reduce major adverse cardiovascular events (MACE), but barriers, including cost, access, and the burden of injections, persist. The SOUL trial marks a significant milestone by evaluating oral semaglutide in high-risk patients, demonstrating a 14% reduction in MACE versus placebo and reinforcing GLP-1RAs cardioprotective potential in an oral formulation. This advancement holds promise for patient populations underrepresented in prior trials. However, gastrointestinal side effects and strict dosing requirements challenge long-term adherence. While the findings suggest improved accessibility and real-world applicability, further comparative trials with injectables, extended follow-up, and cost-effectiveness studies are essential. As evidence evolves, oral GLP-1RAs may represent a more patient-centered approach to managing diabetes and cardiovascular risk. This perspective article aims to explore the implications of the SOUL trial, highlight ongoing challenges in adherence and implementation, and discuss the future role of oral GLP-1RAs in cardiovascular and diabetes care.