MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis.

Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα 1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

Hybrid Hydrogels for Immunoregulation and Proangiogenesis through Mild Heat Stimulation to Accelerate Whole-Process Diabetic Wound Healing.

Intense and persistent oxidative stress, excessive inflammation, and impaired angiogenesis severely hinder diabetic wound healing. Bioactive hydrogel dressings with immunoregulatory and proangiogenic properties have great promise in treating diabetic wounds. However, the therapeutic effects of dressings always depend on drugs with side effects, expensive cytokines, and cell therapies. Herein, a novel dynamic borate-bonds crosslinked hybrid multifunctional hydrogel dressings with photothermal properties are developed to regulate the microenvironment of diabetic wound sites and accelerate the whole process of its healing without additional medication. The hydrogel is composed of phenylboronic acid-modified chitosan and hyaluronic acid (HA) crosslinked by tannic acid (TA) through borate bonds and Prussian blue nanoparticles (PBNPs) with photothermal response characteristics are embedded in the polymer networks. The results indicate hydrogels show inherent broad-spectrum antioxidative activities through the integrated interaction of borate bonds, TA, and PBNPs. Meanwhile, combined with the regulation of macrophage phenotype by HA, the inflammatory microenvironment of diabetic wounds is transformed. Moreover, the angiogenesis is then enhanced by the mild photothermal effect of PBNPs, followed by promoted epithelialization and collagen deposition. In summary, this hybrid hydrogel system accelerates all stages of wound repair through antioxidative stress, immunomodulation, and proangiogenesis, showing great potential applications in diabetic wound management.

Multifunctional Hydrogels for the Healing of Diabetic Wounds.

The healing of diabetic wounds is hindered by various factors, including bacterial infection, macrophage dysfunction, excess proinflammatory cytokines, high levels of reactive oxygen species, and sustained hypoxia. These factors collectively impede cellular behaviors and the healing process. Consequently, this review presents intelligent hydrogels equipped with multifunctional capacities, which enable them to dynamically respond to the microenvironment and accelerate wound healing in various ways, including stimuli -responsiveness, injectable self-healing, shape -memory, and conductive and real-time monitoring properties. The relationship between the multiple functions and wound healing is also discussed. Based on the microenvironment of diabetic wounds, antibacterial, anti-inflammatory, immunomodulatory, antioxidant, and pro-angiogenic strategies are combined with multifunctional hydrogels. The application of multifunctional hydrogels in the repair of diabetic wounds is systematically discussed, aiming to provide guidelines for fabricating hydrogels for diabetic wound healing and exploring the role of intelligent hydrogels in the therapeutic processes.

Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing.

Neovascularization is critical to improve the diabetic microenvironment, deliver abundant nutrients to the wound and promote wound closure. However, the excess of oxidative stress impedes the healing process. Herein, a self-adaptive multifunctional hydrogel with self-healing property and injectability is fabricated through a boronic ester-based reaction between the phenylboronic acid groups of the 3-carboxyl-4-fluorophenylboronic acid -grafted quaternized chitosan and the hydroxyl groups of the polyvinyl alcohol, in which pro-angiogenic drug of desferrioxamine (DFO) is loaded in the form of gelatin microspheres (DFO@G). The boronic ester bonds of the hydrogel can self-adaptively react with hyperglycemic and hydrogen peroxide to alleviate oxidative stress and release DFO@G in the early phase of wound healing. A sustained release of DFO is then realized by responding to overexpressed matrix metalloproteinases. In a full-thickness diabetic wound model, the DFO@G loaded hydrogel accelerates angiogenesis by upregulating expression of hypoxia-inducible factor-1 and angiogenic growth factors, resulting in collagen deposition and rapid wound closure. This multifunctional hydrogel can not only self-adaptively change the microenvironment to a pro-healing state by decreasing oxidative stress, but also respond to matrix metalloproteinases to release DFO. The self-adaptive multifunctional hydrogel has a potential for treating diabetic wounds.

Covalently crosslinked sodium alginate/poly(sodium p-styrenesulfonate) cryogels for selective removal of methylene blue.

Adsorbents with high adsorption capacity, sustainability, and reusability are desired in wastewater treatments. Herein, covalently crosslinked microporous cryogels with efficient removal of cationic dyes are fabricated by freezing radical copolymerization using methacrylated alginate (AlgMA) and sodium p-styrenesulfonate (NaSS). The chemical structure, morphology, and thermal stability of the AlgMA/PNaSS cryogels are characterized. Compared with the AlgMA/PNaSS hydrogels with the same chemical composition fabricated by thermal-initiated polymerization, the cryogels show higher adsorption of methylene blue. The AlgMA/PNaSS (with a mass ratio of 1:2) possesses the maximum adsorption capacity for MB with 2300 mg/g under alkaline condition. In addition, the adsorption process of AlgMA/PNaSS cryogels fits the pseudo-second order model and Freundlich model, respectively. The AlgMA/PNaSS cryogels also reveal selective adsorption capacity and reusability after regeneration, which own unchanged corrected adsorption capacity during five adsorption-desorption cycles. The AlgMA/PNaSS cryogels show great potential for use in wastewater treatments and intelligent separation.