of diabetes mellitus. Globally, these wounds are important causes of disability and mortality. [2] Diabetic wounds that fail to heal are largely caused by oxidative stress. [3] Overproduction of reactive oxygen species (ROS) and inadequate antioxidant protection results in excess oxidative stress, leading to cell apoptosis and suppressed cell proliferation as well as differentiation at diabetic wound sites. [4] In high glucose (HG) conditions, glucotoxicity disrupts angiogenesis, thereby limiting the transport and delivery of nutrients and oxygen in diabetic wounds. [5] Diabetic skin wounds are more susceptible to bacterial infections, causing belated healing and life-threatening outcomes. [6,7] Bacterial infections are also involved in oxidative stress induction. [8] Excess oxidative stress levels suppress growth factor-mediated signaling pathways, resulting in dysregulated angiogenesis. Oxidative stress, angiogenesis, and bacterial infections have been reported to jointly cause diabetic wound healing disorders. [9] The existing therapies include drugs or application of bio-activators, hyperbaric oxygen therapy, and stem cell therapy. [10][11][12] However, these therapies are expensive, single-functional, immature, and cumbersome to operate in many cases. [13,14] The limited efficacies create an urgent need for the development of novel treatment modalities.Microneedle (MN) patches are emerging minimally-invasive local delivery systems that have the ability to overcome the dosing inefficiency of systemic delivery. And the new-generation MN, such as bioinspired or stimuli-responsive MN, exhibits more individualized, more efficient, and more convenient. [15,16] These patches have been applied for the treatment of various diseases, including skin wounds. [17,18] However, the current MN patches cannot act on multiple targets of diabetes wound pathogenesis. [19] We developed a multifunctional MN patch with the ability to simultaneously target oxidative stress, angiogenesis, and bacterial infections in diabetic wounds. A silk fibroin methacryloyl hydrogel was selected as the base material for multifunctional MN patches. Silk fibroin methacryloyl was formed from silk fibroin, a physiologically inactive protein derived from Bombyx mori silkworm cocoon, modified with glycidyl-methacrylate groups to supply a cross-linkage site essential for photopolymerization. Silk fibroin methacryloyl has excellent biocompatibility, biodegradability, stable mechanical Diabetic wound is one of the common complications in diabetic patients, which exhibits chronic, hard-to-heal characteristics. The healing process of wounds is impaired by several factors, including excessive oxidative stress, blocked angiogenesis, and bacterial infection. The therapeutic effects of traditional microneedle patches remain not satisfactory, due to their difficulty simultaneously targeting multiple targets to treat diabetic wounds. As such, there is an urgent need to develop a multifunctional microneedle (MN) patch for promoting the healing of diabetic wounds. ...

Palmitic acid (PA) is the most common saturated long-chain fatty acid that causes damage to heart muscle cells. However, the molecular mechanism of PA toxicity in myocardial cells is not fully understood. In the present study, we explored the effects of PA on proliferation and apoptosis of H9c2 cardiomyocytes, and uncovered the signaling pathways involved in PA toxicity. Our study revealed induction of both oxidative and endoplasmic reticulum (ER) stresses and exacerbation of apoptosis in PA-treated H9c2 cells. Inhibition of oxidative stress by N-acetylcysteine (NAC) reduced apoptosis and decreased ER stress in PA-treated H9c2 cells. Moreover, inhibition of ER stress by 4-phenyl butyric acid decreased apoptosis and attenuated oxidative stress. In summary, the present study demonstrated that oxidative stress coordinates with ER stress to play important roles in PA-induced H9c2 cell apoptosis.

Palmitic acid (PA) is the most common saturated long-chain fatty acid in food that causes cell apoptosis. However, little is known about the molecular mechanisms of PA toxicity. In this study, we explore the effects of PA on proliferation and apoptosis in human osteoblast-like Saos-2 cells and uncover the signaling pathways involved in the process. Our study showed that endoplasmic reticulum (ER) stress and autophagy are involved in PA-induced Saos-2 cell apoptosis. We found that PA inhibited the viability of Saos-2 cells in a dose- and time-dependent manner. At the same time, PA induced the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)), altered autophagy-related gene expression (microtubule-associated protein 1 light chain 3 (LC3), ATG5, p62, and Beclin), promoted apoptosis-related gene expression (Caspase 3 and BAX), and affected autophagic flux. Inhibiting ER stress with 4-PBA diminished the PA-induced cell apoptosis, activated autophagy, and increased the expression of Caspase 3 and BAX. Inhibiting autophagy with 3-MA attenuated the PA and ER stress-induced cell apoptosis and the apoptosis-related gene expression (Caspase 3 and BAX), but seemed to have no obvious effects on ER stress, although the CHOP expression was downregulated. Taken together, our results suggest that PA-induced Saos-2 cell apoptosis is activated via ER stress and autophagy, and the activation of autophagy depends on the ER stress during this process.

Chronic wounds caused by severe trauma remain a serious challenge for clinical treatment. In this study, we developed a novel angiogenic 3D-bioprinted peptide patch to improve skin wound healing. The 3D-bioprinted technology can fabricate individual patches according to the shape characteristics of the damaged tissue. Gelatin methacryloyl (GelMA) and hyaluronic acid methacryloyl (HAMA) have excellent biocompatibility and biodegradability, and were used as a biomaterial to produce bioprinted patches. The pro-angiogenic QHREDGS peptide was covalently conjugated to the 3D-bioprinted GelMA/HAMA patches, extending the release of QHREDGS and improving the angiogenic properties of the patch. Our results demonstrated that these 3D-bioprinted peptide patches showed excellent biocompatibility, angiogenesis, and tissue repair both in vivo and in vitro . These findings indicated that 3D-bioprinted peptide patches improved skin wound healing and could be used in other tissue engineering applications.