Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core-Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation.

Due to the immunosuppressive tumor microenvironment (TME) and weak radiation absorption, the immune response triggered by radiation therapy (RT) is limited. Herein, a core-shell nanosensitizer UiO@MnS (denoted as UM) was genuinely constructed for the amplification of RT efficacy and induction of immunogenicity via integrating MnS-reprogrammed TME with Hf-based UiO-sensitized RT. The acid-sensitive MnS would produce H2S under acidic TME to improve oxygenation through inhibition mitochondrial respiration and reducing metabolic oxygen consumption, leading to decreased HIF-1α expression and enhanced radiosensitization. In addition, the generated H2S inhibited the catalase activity to increase the H2O2 level, which subsequently enhanced the Mn2+-mediated Fenton-like reaction, resulting in G2/M cell cycle arrest to improve the cellular sensitivity for radiation. This impressive tumor oxygenation, cell cycle arrest, and radiosensitization procedure boosted RT efficacy and resulted in strong antitumor immunogenicity. Taken together, combining the immunosuppressive TME modulation with a sensitizing radiation strategy shows great promise for magnifying immunogenic RT outputs.

Hydrogel with ROS scavenging effect encapsulates BR@Zn-BTB nanoparticles for accelerating diabetic mice wound healing via multimodal therapy.

The strategies for eliminating excess reactive oxygen species (ROS) or suppressing inflammatory responses on the wound bed have proven effective for diabetic wound healing. In this work, a zinc-based nanoscale metal-organic framework (NMOF) functions as a carrier to deliver natural product berberine (BR) to form BR@Zn-BTB nanoparticles, which was, in turn, further encapsulated by hydrogel with ROS scavenging ability to yield a composite system of BR@Zn-BTB/Gel (denoted as BZ-Gel). The results show that BZ-Gel exhibited the controlled release of Zn2+ and BR in simulated physiological media to efficiently eliminated ROS and inhibited inflammation and resulted in a promising antibacterial effect. In vivo experiments further proved that BZ-Gel significantly inhibited the inflammatory response and enhanced collagen deposition, as well as to re-epithelialize the skin wound to ultimately promote wound healing in diabetic mice. Our results indicate that the ROS-responsive hydrogel coupled with BR@Zn-BTB synergistically promotes diabetic wound healing.

A pH-responsive metal-organic framework for the co-delivery of HIF-2α siRNA and curcumin for enhanced therapy of osteoarthritis.

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

[Experimental study on anaphylactoid reactions induced by different components of shengmai injection (new production process) on Beagle dogs].

OBJECTIVE: To evaluate the sensitization effect of different components of Shengmai injection (new production process) on Beagle dogs. METHOD: Beagle dogs were randomly divided into 7 groups, 3 in each group. Each group was respectively injected with 5% glucose injection, Ginseng Radix et Rhizoma Rubra extract, Ophiopogonis Radix extract, Schisandrae Chinensis Fructus extract, Schisandrae Chinersis Fructus distillate, Shengmaifang, 0.2% tween 80. The changes of each dog were observed from injection before until 24 hours after injection, and the response level was determined according to the severity of the symptoms. Blood samples were collected before injection and at 10 min after injection for measuring histamine content in plasma by ELISA. Sensitization of the injection was comprehensively determined by combined the response level of symptoms and the histamine level. RESULT: One dog of Ginseng Radix et Rhizoma Rubra extract group showed untypical symptoms of anaphylactoid reactions, and serum histamine of two dogs increased more than doubled. The Beagle dogs administrated with 0.2% tween 80 showed typical symptoms of anaphylactoid reactions, while there was no significant increase of serum histamine. Other groups were observed with no typical anaphylactoid reactions. CONCLUSION: The sensitization effect of Shengmai injection (new production process) may be associated with Ginseng Radix et Rhizoma Rubra extract and 0.2% tween 80.

[Experimental study on anaphylactoid reactions induced by shengmai injection (new production process) on Cynomolgus monkey].

OBJECTIVE: To compare the anaphylactoid effect of old Shengmai injection and new Shengmai injection on Cynomolgus monkey. METHOD: Cynomolgus monkeys were randomly divided into 4 groups, and were respectively injected with 5% glucose injection, old Shengmai injection, new Shengmai injection, positive control drug. The changes of each monkey were observed from injection before until 24 hours after injection, and the response level was determined according to the severity of the symptoms. Blood samples were collected before injection and at 10 min after injection for measuring histamine content in plasma. Blood pressure and heart rates were detected before injection and at 10 min after injection. Sensitization of the injection was comprehensively determined by combined the response level of symptoms and the histamine level. RESULT: The Cynomolgus monkeys administrated with old Shengmai injection showed typical symptoms of anaphylactoid reactions and the content of serum histamine is not more than doubled. The Cynomolgus monkeys administrated with new Shengmai injection showed untypical symptoms of anaphylactoid reactions and the content of serum histamine did not rise. CONCLUSION: The old Shengmai injection can induce typical anaphylactoid reactions on Cynomolgus monkeys, and the sensitization ability is strong. The symptoms of anaphylactoid reactions induced by the new Shengmai injection appeared later and showed lesser degree with the sensitization lower.

[Experimental study on anaphylactoid reactions of guinea pig induced by danshen injection and its components].

OBJECTIVE: To compare the anaphylactoid effect of Danshen injection and its components on guinea pig. METHOD: Applying active systemic anaphylaxis (ASA) tests, the corresponding experimental injections were administrated to guinea pigs to sensitized, and allergen with double doses was injected to stimulate in the 11 days after the last sensitized. The anaphylaxis situation of guinea pigs was observed. RESULT: Danshen injection and its components are suspicion on guinea pigs, while negative reaction was observed on guinea pigs which injected by the liquid excipients of Danshen injection. CONCLUSION: Danshen injection using the ultrafiltration method still have some antigenic impurities which cannot be removed completely, and this may be one of the reasons for anaphylactic reaction.