Vascularized liver-on-a-chip model to investigate nicotine-induced dysfunction.

The development of physiologically relevant in vitro systems for simulating disease onset and progression and predicting drug metabolism holds tremendous value in reducing drug discovery time and cost. However, many of these platforms lack accuracy in replicating the tissue architecture and multicellular interactions. By leveraging three-dimensional cell culture, biomimetic soft hydrogels, and engineered stimuli, in vitro models have continued to progress. Nonetheless, the incorporation of the microvasculature has been met with many challenges, specifically with the addition of parenchymal cell types. Here, a systematic approach to investigating the initial seeding density of endothelial cells and its effects on interconnected networks was taken and combined with hepatic spheroids to form a liver-on-a-chip model. Leveraging this system, nicotine's effects on microvasculature and hepatic function were investigated. The findings indicated that nicotine led to interrupted adherens junctions, decreased guanosine triphosphate cyclohydrolase 1 expression, impaired angiogenesis, and lowered barrier function, all key factors in endothelial dysfunction. With the combination of the optimized microvascular networks, a vascularized liver-on-a-chip was formed, providing functional xenobiotic metabolism and synthesis of both albumin and urea. This system provides insight into potential hepatotoxicity caused by various drugs and allows for assessing vascular dysfunction in a high throughput manner.

RPA facilitates rescue of keratinocytes from UVB radiation damage through insulin-like growth factor-I signalling.

UVBR-induced photolesions in genomic DNA of keratinocytes impair cellular functions and potentially determine the cell fate post-irradiation. The ability of insulin-like growth factor-I (IGF-I) to rescue epidermal keratinocytes after photodamage via apoptosis prevention and photolesion removal was recently demonstrated using in vitro two-dimensional and three-dimensional skin models. Given the limited knowledge of specific signalling cascades contributing to post-UVBR IGF-I effects, we used inhibitors to investigate the impact of blockade of various signalling mediators on IGF-I photoprotection. IGF-I treatment, in the presence of signalling inhibitors, particularly TDRL-505, which targets replication protein A (RPA), impaired activation of IGF-1R downstream signalling, diminished cyclobutane pyrimidine dimer removal, arrested growth, reduced cell survival and increased apoptosis. Further, the transient partial knockdown of RPA was found to abrogate IGF-I-mediated responses in keratinocytes, ultimately affecting photoprotection and, thereby, establishing that RPA is required for IGF-I function. Our findings thus elucidate the importance of RPA in linking the damage response activation, cell cycle regulation, repair and survival pathways, separately initiated by IGF-I upon UVBR-induced damage. This information is potentially imperative for the development of effective sunburn and photodamage repair strategies. This article has an associated First Person interview with the first author of the paper.

Insulin-like growth factor-I rescue of primary keratinocytes from pre- and post-ultraviolet B radiation effects.

Ultraviolet B radiation (UVBR) induces the formation of photolesions in epidermal keratinocytes, potentially affecting cellular function and contributing towards malignant transformation. Insulin-like growth factor-I (IGF-I) contributes to protection of keratinocytes against UVBR-induced damage. Studies have shown that exogenous IGF-I or dermal fibroblast conditioned media pre-UVBR contributes to protection in primary keratinocytes by preventing apoptosis, modulating cell cycle progression and affecting photolesion removal through its damage preventative effects, however, the efficacy of IGF-I post-UVBR has not been sufficiently addressed. Using 2D and 3D photobiology skin models, the ability of IGF-I post-UVBR to rescue primary keratinocytes from photodamage was investigated. The photoprotective effect of IGF-I, both pre- and post-UVBR on cellular functions of irradiated keratinocytes was examined. IGF-I application, either pre- or post-UVBR, was found to alter keratinocyte survival, apoptosis, cell cycle progression and damage removal responses to UVBR. In particular, IGF-I application post-UVBR was found to promote increased keratinocyte survival, prevent apoptosis, shift cell cycle progression and reduce photodamage in all the skin models. Furthermore, marked differences were observed in activation of signalling cascades upon IGF-I treatment post-UVBR. Taken together, these findings indicate that in addition to a previously known photodamage preventative effect, IGF-I treatment post-UVBR has a photoreparative role suggesting it may hold potential in the development of effective remedial strategies against sunburns and photodamage.

Unravelling the insulin-like growth factor I-mediated photoprotection of the skin.

Chronic exposure of human skin to solar ultraviolet radiation (UVR) induces a range of biological reactions which may directly or indirectly lead to the development of skin cancer. In order to overcome these damaging effects of UVR and to reduce photodamage, the skin's endogenous defence system functions in concert with the various exogenous photoprotectors. Growth factors, particularly insulin-like growth factor-I (IGF-I), produced within the body as a result of cellular interaction in response to UVR demonstrates photoprotective properties in human skin. This review summarises the impact of UVR-induced photolesions on human skin, discusses various endogenous as well as exogenous approaches of photoprotection described to date and explains how IGF-I mediates UVR photoprotective responses at the cellular and mitochondrial level. Further, we describe the current interventions using growth factors and propose how the knowledge of the IGF-I photoprotection signalling cascades may direct the development of improved UVR protection and remedial strategies.

Antibiotics-Induced Obesity: A Mitochondrial Perspective.

Antibiotics are the first line of treatment against infections and have contributed immensely to reduce the morbidity and mortality rates. Recently, extensive use of antibiotics has led to alterations of the gut microbiome, predisposition to various diseases and most importantly, increase in the emergence of antibiotic-resistant bacteria, which poses a major threat to global public health. Another major issue faced worldwide due to unregulated use of antibiotics in children as well as in adults is the influence of metabolism and body weight homeostasis, leading to obesity. Apart from the involvement of biosocial causes influencing diet, physical activity, and antibiotic use, pathogenesis of obesity is linked to interconnected functional alterations in cells, tissues and organs due to biochemical, epigenetic and genetic factors. Mitochondrial dysfunction is one such factor, which is becoming the primary focus of various aspects of research on multifactorial complex diseases and is providing new perspectives on etiology, biomarker-based diagnosis, and drug sensitivity. Through this review, we have made an attempt to present the interplay between use of antibiotics, obesity, and associated mitochondrial dysfunction. This may provide insights into the molecular basis, genetic predisposition and environmental triggers, which in turn may have potential clinical applications in the management of antibiotic use.