Generation of reactive oxygen species, delayed blood clotting, prolonged inflammation, bacterial infection, and slow cell proliferation are the main challenges of effective wound repair. Herein, a multifunctional extracellular matrix‐mimicking hydrogel is fabricated through abundant hydrogen bonding among the functional groups of gelatin and tannic acid (TA) as a green chemistry approach. The hydrogel shows adjustable physicochemical properties by altering the concentration of TA and it represents high safety features both in vitro and in vivo on fibroblasts, red blood cells, and mice organs. In addition to the merit of facile encapsulation of cell proliferation‐inducing hydrophilic drugs, accelerated healing of skin injury is obtained through pH‐dependent release of TA and its multifaceted mechanisms as an antibacterial, antioxidant, hemostatic, and anti‐inflammatory moiety. The developed gelatin‐TA (GelTA) hydrogel also shows an outstanding effect on the formation of extracellular matrix and wound closure in vivo via offered cell adhesion sites in the backbone of gelatin that provide increased re‐epithelialization and better collagen deposition. These results suggest that the multifunctional GelTA hydrogel is a promising candidate for the clinical treatment of full‐thickness wounds and further development of wound dressing materials that releases active agents in the neutral or slightly basic environment of infected nonhealing wounds.

Due to the synergic feature of individual components in hybrid (nano)biomaterials, their application in regenerative medicine has drawn significant attention. Aiming to address all the current challenges of aerogel as a potent scaffold in bone tissue engineering application, we adopted a novel synthesis approach to synergistically improve the pore size regime and mechanical strength in the aerogel. The three-dimensional aerogel scaffold in this study has been synthesized through a versatile one-pot aqueous-based sol−gel hybridization/assembly of organosilane (tetraethyl orthosilicate) and silk fibroin (SF) biopolymer, followed by unidirectional freeze-casting of the as-prepared hybrid gel and supercritical drying. The developed ultralight silica-SF aerogel hybrids demonstrated a hierarchically organized porous structure with interesting honeycomb-shaped micromorphology and microstructural alignment (anisotropy) in varied length scales. The average macropore size of the hybrid aerogel lied in ∼0.5−18 μm and was systematically controlled with freeze-casting conditions. Together with high porosity (91−94%), high Young's modulus (∼4−7 MPa, >3 order of magnitude improvement compared to their pristine aerogel counterparts), and bone-type anisotropy in the mechanical compressive behavior, the silica-SF hybrid aerogel of this study acted as a very competent scaffold for bone tissue formation. The results of in vitro assessments revealed that the silica-SF aerogel is not only cytocompatible and nonhemolytic but also acted as an open porous microenvironment to trigger osteoblast cell attachment, growth, and proliferation on its surface within 14 days of incubation. Moreover, to support the in vitro results, in vivo bone formation within the aerogel implant in the bone defect site was studied. The X-ray radiology and microcomputed tomography analyses confirmed that a significant new bone tissue density formed in the defect site within 25 days of implantation. Also, in vivo toxicology studies showed a zero-toxic impact of the aerogel implant on the blood biochemical and hematological parameters. Finally, the study clearly shows the potential of aerogel as a bioactive and osteoconductive open porous cellular matrix for a successful osseointegration process.

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1. 5-Fluorouracil (5-FU) and its prodrug capecitabine are key chemotherapeutic agents in the treatment of many gastrointestinal tract adenocarcinomas. In addition to their beneficial antitumor effects, they also possess undesired cardiac toxicity. In the present study, we investigated the cytotoxic mechanisms of 5-FU and capecitabine in freshly isolated rat cardiomyocytes. 2. 5-FU and capecitabine cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione depletion. Increased intracellular ROS could target mitochondria, and our findings confirmed that the cardiomyocytes mitochondrial membrane potential (ΔΨm) was rapidly decreased by 5-FU and capecitabine. Mitochondrial dysfunction subsequently initiates downstream events that trigger caspase-3 activation, and our results showed that 5-FU and capecitabine activated caspase-3 which leads to apoptosis or necrosis. However, 5-FU acted much more powerful than capecitabine at inducing several cytotoxicity markers in heart cardiomyocytes. In addition, 5-FU but not capecitabine caused lysosomal membrane leakiness when it was incubated with cardiomyocytes. All cytotoxicity markers were prevented by antioxidants, ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents and lysosomotropic agents. 3. Our findings showed that the cytotoxic action of 5-FU and capecitabine on cardiomyocytes are mediated by oxidative stress and subsequent mitochondrial dysfunction which causes caspase-3 activation and cell death.

Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 μM) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.