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Upon injury, nearby cells, including fibroblasts at the wound edge, are often found in a hypoxic microenvironment. Nevertheless, the influence of hypoxia on skin fibroblasts is poorly understood. Using previously established mouse full‐thickness wounds, we show that Bcl‐2 and adenovirus E1B 19‐kDa interacting protein 3 (BNIP3) expression was significantly elevated at the wound edge, and hypoxia treatment enhanced BNIP3 expression in fibroblasts. Interestingly, BNIP3 promoted the migration and proliferation, as well as the activation of autophagy, in fibroblasts under hypoxia. The hypoxia‐induced autophagy was found to induce the migration and proliferation of fibroblasts, a process that could be reversed by knocking down the autophagy‐related gene for autophagy protein 5, ATG5. Furthermore, hypoxia‐inducible factor 1 subunit alpha (HIF‐1α) was significantly upregulated in fibroblasts under hypoxia treatment, and HIF‐1α knockdown attenuated the hypoxia‐induced expression of BNIP3 and the migration and proliferation of fibroblasts. Altogether, our results establish the hypoxia‐BNIP3‐autophagy signaling axis as a newly identified regulatory mechanism of skin fibroblast migration and proliferation upon wounding. Autophagy intervening might thus represent a promising therapeutic strategy for patients with chronic refractory wounds. [ABSTRACT FROM AUTHOR]

Although near‐infrared (NIR) light‐based photothermal therapies have shown therapeutic potential for infected wounds, the attenuation of NIR light intensity in tissue has severely limited the usage in deep bacterial infections. Herein, magneto‐thermal responsive bilayer microneedles (Fe‐Se‐HA MNs) consisting of functionalized hyaluronic acid (HA), ferro‐ferric oxide (Fe3O4), and micelle‐protected selenium nanoparticles (SeNPs@LAS) are constructed to overcome this challenge based on a self‐designed disk‐shaped electromagnetic field device (Disk‐ZVS). The electromagnetic field generated by the Disk‐ZVS shows virtually no intensity attenuation in living tissue. Finite element simulations showed that the field intensity and electromagnetic loss are concentrated on the tips of Fe‐Se‐HA MNs. The MNs are able to puncture hard scabs, penetrate into bacterial biofilms, and perform effective magnetic‐thermal conversion for deep hyperthermia sterilization. Following, the Fe‐Se‐HA MNs can be gradually degraded by excessive hyaluronidase in diabetic wound to release SeNPs, which reduce reactive oxygen species (ROS) to regulate wound redox homeostasis. Meanwhile, the SeNPs are beneficial to angiogenesis, which facilitates blood vessel formation and promotes wound repair. Therefore, various functions can be achieved for the Fe‐Se‐HA MNs, such as magneto‐thermal disinfection, deep and non‐invasive tissue penetration, anti‐inflammation, and pro‐angiogenesis, which shows great potential as an adjunctive therapy for infected diabetic wounds. [ABSTRACT FROM AUTHOR]

The migration of keratinocytes from wound margins plays a critical role in the re-epithelialization of skin wounds. Hypoxia occurs immediately after injury and acts as an early stimulus to initiate the healing processes. Although our previous studies have revealed that hypoxia promotes keratinocyte migration, the precise mechanisms involved remain unclear. Here, we found that BNIP3 expression was upregulated in hypoxic keratinocytes, and BNIP3 silencing suppressed hypoxia-induced cell migration. Additionally, hypoxia activated the focal adhesion kinase ( FAK) pathway through upregulation of BNIP3, while FAK inhibition attenuated hypoxic keratinocyte migration. Here, we conclusively demonstrate a novel role for BNIP3 in hypoxia-induced keratinocyte migration. Furthermore, we provide a new perspective on the molecular mechanisms of wound healing and identify BNIP3 as a potential new molecular target for clinical treatments to enhance wound healing. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved self-protection mechanism that plays a crucial role in cardiovascular diseases. Cardiomyocyte hypoxic injury promotes oxidative stress and pathological alterations in the heart, although the interplay between these effects remains elusive. The transient receptor potential vanilloid 1 (TRPV1) ion channel is a nonselective cation channel that is activated in response to a variety of exogenous and endogenous physical and chemical stimuli. Here, we investigated the effects and mechanisms of action of TRPV1 on autophagy in hypoxic cardiomyocytes. In this study, primary cardiomyocytes isolated from C57 mice were subjected to hypoxic stress, and their expression of TRPV1 and adenosine 5'-monophosphate-activated protein kinase (AMPK) was regulated. The autophagy flux was assessed by Western blotting and immunofluorescence staining, and the cell viability was determined through Cell counting kit-8 assay and Lactate dehydrogenase assays. In addition, the calcium influx after the upregulation of TRPV1 expression in cardiomyocytes was examined. The results showed that the number of autophagosomes in cardiomyocytes was higher under hypoxic stress and that the blockade of autophagy flux aggravated hypoxic damage to cardiomyocytes. Moreover, the expression of TRPV1 was induced under hypoxic stress, and its upregulation by capsaicin improved the autophagy flux and protected cardiomyocytes from hypoxic damage, whereas the silencing of TRPV1 significantly attenuated autophagy. Our observations also revealed that AMPK signaling was activated and involved in TRPV1-induced autophagy in cardiomyocytes under hypoxic stress. Overall, this study demonstrates that TRPV1 activation mitigates hypoxic injury in cardiomyocytes by improving autophagy flux through the AMPK signaling pathway and highlights TRPV1 as a novel therapeutic target for the treatment of hypoxic cardiac disease.

Endogenous wound electric fields (EFs), an important and fundamental occurrence of wound healing, profoundly influence the directed migration of keratinocytes. Although numerous studies have unveiled the signals responsible for EF-biased direction, the mechanisms by which EFs promote keratinocyte motility remains to be elucidated. In our study, EFs enhanced the directed migratory speed of keratinocytes by inducing autophagic activity, thereby facilitating skin barrier restoration. Initially, we found that electrical signals directed keratinocytes to the cathode with enhanced motility parameters [ i.e., trajectory distance, trajectory speed, displacement distance, and displacement speed ( T d / t)] and more efficient migration (directionality and T d / t along the x axis, among others). Meanwhile, EFs induced a time-dependent increase in autophagic activity in keratinocytes, with constant autophagic flux, accompanied by increased transcription of numerous autophagy-related genes. Deficiency in Atg5, a key protein necessary for autophagosome formation, led to significant reduction of autophagy, which was accompanied by a substantial reduction in EF-stimulated directed motility. These results demonstrated a causal relationship between autophagy and EF-directed migratory speed. In addition, both cell migration under normal conditions and EF-biased directionality were autophagy independent. Thus, our findings define autophagy as an important functional regulator of electrically enhanced directed motility, adding to a growing understanding of EFs.-Yan, T., Jiang, X., Lin, G., Tang, D., Zhang, J., Guo, X., Zhang, D., Zhang, Q., Jia, J., Huang, Y. Autophagy is required for the directed motility of keratinocytes driven by electric fields.