[Effect of Gegen Qinlian Decoction on cardiac diastolic function of diabetic mice with damp-heat syndrome].

This study was designed to explore the effect and mechanism of Gegen Qinlian Decoction(GQD) on cardiac function of diabetic mice with damp-heat syndrome. The db/db diabetic mice were exposed to the damp-heat environment test chamber for inducing the damp-heat syndrome. Forty-eight six-week-old db/db mice were randomly divided into six groups, namely the db/db diabetic model group, db/db diabetic mouse with damp-heat syndrome(db/db-dh) group, db/db diabetic mouse with damp-heat syndrome treated with low-dose GQD(db/db-dh+GQD-L) group, db/db-dh+GQD-M(medium-dose) group, db/db-dh+GQD-H(high-dose) group, and db/db-dh+lipro(liprostatin-1, the inhibitor of ferroptosis) group, with eight six-week-old db/m mice classified into the control group. The results showed that mice presented with the damp-heat syndrome after exposure to the "high-fat diet" and "damp-heat environment", manifested as the elevated fasting blood glucose, reduced food intake, low urine output, diarrhea, listlessness, loose and coarse hair, and dark yellow and lusterless fur. However, the intragastric administration of the high-dose GQD for 10 weeks ameliorated the above-mentioned symptoms, inhibited myocardial hypertrophy and fibrosis, and improved the cardiac diastolic function of db/db-dh mice. qPCR suggested that GQD regulated the expression of ferroptosis-related genes, weakened the lipid peroxidation in the myocardium, and up-regulated glutathione peroxidase 4(GPX4) expression in comparison with those in the db/db-dh group. At the same time, the ferroptosis inhibitor liprostatin-1 significantly improved the cardiac function and reversed the cardiac remodeling of db/db-dh mice. It can be concluded that the damp-heat syndrome may aggravate myocardial ferroptosis and accelerate cardiac remodeling of db/db mice, thus leading to diastolic dysfunction. GQD is able to improve cardiac remodeling and diastolic function in diabetic mice with damp-heat syndrome, which may be related to its inhibition of myocardial ferroptosis.

The recent progress on metal-organic frameworks for phototherapy.

Some infectious or malignant diseases such as cancers are seriously threatening the health of human beings all over the world. The commonly used antibiotic therapy cannot effectively treat these diseases within a short time, and also bring about adverse effects such as drug resistance and immune system damage during long-term systemic treatment. Phototherapy is an emerging antibiotic-free strategy to treat these diseases. Upon light irradiation, phototherapeutic agents can generate cytotoxic reactive oxygen species (ROS) or induce a temperature increase, which leads to the death of targeted cells. These two kinds of killing strategies are referred to as photodynamic therapy (PDT) and photothermal therapy (PTT), respectively. So far, many photo-responsive agents have been developed. Among them, the metal-organic framework (MOF) is becoming one of the most promising photo-responsive materials because its structure and chemical compositions can be easily modulated to achieve specific functions. MOFs can have intrinsic photodynamic or photothermal ability under the rational design of MOF construction, or serve as the carrier of therapeutic agents, owing to its tunable porosity. MOFs also provide feasibility for various combined therapies and targeting methods, which improves the efficiency of phototherapy. In this review, we firstly investigated the principles of phototherapy, and comprehensively summarized recent advances of MOF in PDT, PTT and synergistic therapy, from construction to modification. We expect that our demonstration will shed light on the future development of this field, and bring it one step closer to clinical trials.

Ultrasonic Interfacial Engineering of Red Phosphorous-Metal for Eradicating MRSA Infection Effectively.

Sonodynamic therapy (SDT) is considered to be a potential treatment for various diseases including cancers and bacterial infections due to its deep penetration ability and biosafety, but its SDT efficiency is limited by the hypoxia environment of deep tissues. This study proposes creating a potential solution, sonothermal therapy, by developing the ultrasonic interfacial engineering of metal-red phosphorus (RP), which has an obviously improved sonothermal ability of more than 20 °C elevation under 25 min of continuous ultrasound (US) excitation as compared to metal alone. The underlying mechanism is that the mechanical energy of the US activates the motion of the interfacial electrons. US-induced electron motion in the RP can efficiently transfer the US energy into phonons in the forms of heat and lattice vibrations, resulting in a stronger US absorption of metal-RP. Unlike the nonspecific heating of the cavitation effect induced by US, titanium-RP can be heated in situ when the US penetrates through 2.5 cm of pork tissue. In addition, through a sonothermal treatment in vivo, bone infection induced by multidrug-resistant Staphylococcus aureus (MRSA) is successfully eliminated in under 20 min of US without tissue damage. This work provides a new strategy for combating MRSA by strong sonothermal therapy through US interfacial engineering.

Photoelectrons Mediating Angiogenesis and Immunotherapy through Heterojunction Film for Noninvasive Disinfection.

A light-inspired hydroxyapatite (Hap)/nitrogen-doped carbon dots (NCDs) modified graphene oxide (GO) heterojunction film is developed, which shows a promoted separation of interfacial electrons and holes and an inhibited recombination efficiency via hole depletion. The metabolism of bacteria on this film is significantly inhibited under light irradiation, due to the enhanced photocatalytic and photothermal effects. In addition, the electron transfer from the plasmonic membrane to the GO/NCD/Hap film further inhibits the adenosine triphosphate process of bacteria, thus leading to the synergetic antibacterial efficacy. Meanwhile, the electron transfer between film and cell membrane induces the Ca2+ flow after irradiation, which can promote the migration and proliferation of cells and alkaline phosphatase enhancement, thus favoring the tissue reconstruction. An in vivo test discloses that the vascular injury repair is achieved through the Ca2+-activated PLCγ1/ERK pathway, identified by the enhanced CD31 expression. Moreover, the increased CD4+/CD8+ lymphocytes are ameliorative by activating the PI3K/P-AKT pathway. Consequently, the electron transfer boosts the synergic photodynamic and photothermal therapeutic effects for bacterial infection by Ca2+ flow for immunotherapy. This mild phototherapy approach with GO/NCDs/Hap, which can simultaneously repair injured vessels and relieve inflammation reactions, will increase the clinical application of noninvasive phototherapy in the near future.

Treatment of MRSA-infected osteomyelitis using bacterial capturing, magnetically targeted composites with microwave-assisted bacterial killing.

Owing to the poor penetration depth of light, phototherapy, including photothermal and photodynamic therapies, remains severely ineffective in treating deep tissue infections such as methicillin-resistant Staphylococcus aureus (MRSA)-infected osteomyelitis. Here, we report a microwave-excited antibacterial nanocapturer system for treating deep tissue infections that consists of microwave-responsive Fe3O4/CNT and the chemotherapy agent gentamicin (Gent). This system, Fe3O4/CNT/Gent, is proven to efficiently target and eradicate MRSA-infected rabbit tibia osteomyelitis. Its robust antibacterial effectiveness is attributed to the precise bacteria-capturing ability and magnetic targeting of the nanocapturer, as well as the subsequent synergistic effects of precise microwaveocaloric therapy from Fe3O4/CNT and chemotherapy from the effective release of antibiotics in infection sites. The advanced target-nanocapturer of microwave-excited microwaveocaloric-chemotherapy with effective targeting developed in this study makes a major step forward in microwave therapy for deep tissue infections.

Near-Infrared Light Triggered Phototherapy and Immunotherapy for Elimination of Methicillin-Resistant Staphylococcus aureus Biofilm Infection on Bone Implant.

Clinically, methicillin-resistant Staphylococcus aureus (MRSA) biofilm infection inevitably induces the failure of bone implants. Herein, a hydrophilic and viscous hydrogel of poly(vinyl alcohol) modified with chitosan, polydopamine, and NO release donor was formed on a red phosphorus nanofilm deposited on a titanium implant (Ti-RP/PCP/RSNO). Under the irradiation of near-infrared light (NIR), peroxynitrite (•ONOO-) was formed by the reaction between the released NO and superoxide (•O2-) produced by the RP nanofilm. Specifically, we revealed the antibacterial mechanism of the ONOO- against the MRSA biofilm. In addition, osteogenic differentiation was promoted and inflammatory polarization was regulated by the released NO without NIR irradiation through upregulating the expression of Opn and Ocn genes and TNF-α. The MRSA biofilm was synergistically eradicated by •ONOO-, hyperthermia, and •O2- under NIR irradiation as well as the immunoreaction of the M1 polarization. The in vivo results also confirmed the excellent osteogenesis and biofilm eradication by released NO from the RP/PCP/RSNO system under NIR irradiation, indicating the noninvasive tissue reconstruction of MRSA-infected tissues through phototherapy and immunotherapy.

Highly Effective and Noninvasive Near-Infrared Eradication of a Staphylococcus aureus Biofilm on Implants by a Photoresponsive Coating within 20 Min.

Biofilms have been related to the persistence of infections on medical implants, and these cannot be eradicated because of the resistance of biofilm structures. Therefore, a biocompatible phototherapeutic system is developed composed of MoS2, IR780 photosensitizer, and arginine-glycine-aspartic acid-cysteine (RGDC) to safely eradicate biofilms on titanium implants within 20 min. The magnetron-sputtered MoS2 film possesses excellent photothermal properties, and IR780 can produce reactive oxygen species (ROS) with the irradiation of near-infrared (NIR, λ = 700-1100 nm) light. Consequently, the combination of photothermal therapy (PTT) and photodynamic therapy (PDT), assisted by glutathione oxidation accelerated by NIR light, can provide synergistic and rapid killing of bacteria, i.e., 98.99 ± 0.42% eradication ratio against a Staphylococcus aureus biofilm in vivo within 20 min, which is much greater than that of PTT or PDT alone. With the assistance of ROS, the permeability of damaged bacterial membranes increases, and the damaged bacterial membranes become more sensitive to heat, thus accelerating the leakage of proteins from the bacteria. In addition, RGDC can provide excellent biosafety and osteoconductivity, which is confirmed by in vivo animal experiments.

Lysozyme-Assisted Photothermal Eradication of Methicillin-Resistant Staphylococcus aureus Infection and Accelerated Tissue Repair with Natural Melanosome Nanostructures.

Patients often face the challenge of antibiotic-resistant bacterial infections and lengthy tissue reconstruction after surgery. Herein, human hair-melanosome derivatives (HHMs), comprising keratins and melanins, are developed using a simple "low-temperature alkali heat" method for potentially personalized therapy. The mulberry-shaped HHMs have an average width of ∼270 nm and an average length of ∼700 nm, and the negatively charged HHMs can absorb positively charged Lysozyme (Lyso) to form the HHMs-Lyso composites through electrostatic interaction. These naturally derived biodegradable nanostructures act as exogenous killers to eliminate methicillin-resistant Staphylococcus aureus (MRSA) infection with a high antibacterial efficacy (97.19 ± 2.39%) by synergistic action of photothermy and "Lyso-assisted anti-infection" in vivo. Additionally, HHMs also serve as endogenous regulators of collagen alpha chain proteins through the "protein digestion and absorption" signaling pathway to promote tissue reconstruction, which was confirmed by quantitative proteomic analysis in vivo. Notably, the 13 upregulated collagen alpha chain proteins in the extracellular matrix (ECM) after HHMs treatment demonstrated that keratin from HHMs in collagen-dependent regulatory processes serves as a notable contributor to augmented wound closure. The current paradigm of natural material-tissue interaction regulates the cell-ECM interaction by targeting cell signaling pathways to accelerate tissue repair. This work may provide insight into the protein-level pathways and the potential mechanisms involved in tissue repair.

Rapid and Superior Bacteria Killing of Carbon Quantum Dots/ZnO Decorated Injectable Folic Acid-Conjugated PDA Hydrogel through Dual-Light Triggered ROS and Membrane Permeability.

One of the most difficult challenges in the biomedical field is bacterial infection, which causes tremendous harm to human health. In this work, an injectable hydrogel is synthesized through rapid assembly of dopamine (DA) and folic acid (FA) cross-linked by transition metal ions (TMIs, i.e., Zn2+ ), which was named as DFT-hydrogel. Both the two carboxyl groups in the FA molecule and catechol in polydopamine (PDA) easily chelates Zn2+ to form metal-ligand coordination, thereby allowing this injectable hydrogel to match the shapes of wounds. In addition, PDA in the hydrogel coated around carbon quantum dot-decorated ZnO (C/ZnO) nanoparticles (NPs) to rapidly generate reactive oxygen species (ROS) and heat under illumination with 660 and 808 nm light, endows this hybrid hydrogel with great antibacterial efficacy against Staphylococcus aureus (S. aureus, typical Gram-positive bacteria) and Escherichia coli (E. coli, typical Gram-negative bacteria). The antibacterial efficacy of the prepared DFT-C/ZnO-hydrogel against S. aureus and E. coli under dual-light irradiation is 99.9%. Importantly, the hydrogels release zinc ions over 12 days, resulting in a sustained antimicrobial effect and promoted fibroblast growth. Thus, this hybrid hydrogel exhibits great potential for the reconstruction of bacteria-infected tissues, especially exposed wounds.

Electroacupuncture Preconditioning Improves Myocardial Infarction Injury via Enhancing AMPK-Dependent Autophagy in Rats.

BACKGROUND: Electroacupuncture (EA) pretreatment plays a protective role in myocardial infarction injury. However, the mechanism of electroacupuncture remains unknown. The aim of this study was to confirm the protective effects of electroacupuncture (EA) on myocardial infarction injury and the possible mechanism. METHODS: Sprague-Dawley (SD) rats, used to serve as acute myocardial infarction (AMI) model, were divided into sham group, model (M) group, M+EA group, AMPK inhibitor Compound C (M+EA+CC), and AMPK inhibitor solvent control (M+EA+DMSO) group, respectively. Rats in EA group were pretreated with EA and those in M+EA+CC group with intravenous AMPK inhibitor Compound C. The myocardial morphological changes and infarct size were observed through HE staining and TTC staining, and the concentrations of CK-MB and LDH were detected using ELISA kits. Transmission electron microscopy was employed to observe the autophagosome formation, and the AMPK-dependent autophagy-related protein expression was detected by immunohistochemistry and western blot. RESULTS: EA could alleviate myocardial infarction injury and decrease the concentrations of CK-MB and LDH. Transmission electron microscopy showed that EA could also regulate the AMPK-dependent autophagosome formation and the AMPK-dependent autophagy-related protein expression. AMPK inhibitor Compound C could impair the effect of EA through regulating the concentrations of CK-MB and LDH, autophagosome formation, and autophagy-related protein expression. CONCLUSION: These results indicated that electroacupuncture could improve myocardial infarction injury and induce autophagy, and AMPK-dependent autophagy might be involved in this process.

Rapid Biofilm Eradication on Bone Implants Using Red Phosphorus and Near-Infrared Light.

Bone-implant-associated infections are common after orthopedic surgery due to impaired host immune response around the implants. In particular, when a biofilm develops, the immune system and antibiotic treatment find it difficult to eradicate, which sometimes requires a second operation to replace the infected implants. Most strategies have been designed to prevent biofilms from forming on the surface of bone implants, but these strategies cannot eliminate the biofilm when it has been established in vivo. To address this issue, a nonsurgical, noninvasive treatment for biofilm infection must be developed. Herein, a red-phosphorus-IR780-arginine-glycine-aspartic-acid-cysteine coating on titanium bone implants is prepared. The red phosphorus has great biocompatibility and exhibits efficient photothermal ability. The temperature sensitivity of Staphylococcus aureus biofilm is enhanced in the presence of singlet oxygen (1 O2 ) produced by IR780. Without damaging the normal tissue, the biofilm can be eradicated through a safe near-infrared (808 nm) photothermal therapy at 50 °C in vitro and in vivo. This approach reaches an antibacterial efficiency of 96.2% in vivo with 10 min of irradiation at 50 °C. Meanwhile, arginine-glycine-aspartic-acid-cysteine decorated on the surface of the implant can improve the cell adhesion, proliferation, and osteogenic differentiation.

In Situ Disinfection through Photoinspired Radical Oxygen Species Storage and Thermal-Triggered Release from Black Phosphorous with Strengthened Chemical Stability.

Photodynamic therapy (PDT) utilizing light-induced reactive oxygen species (ROS) is a promising alternative to combat antibiotic-resistant bacteria and biofilm. However, the photosensitizer (PS)-modified surface only exhibits antibacterial properties in the presence of light. It is known that extended photoirradiation may lead to phototoxicity and tissue hypoxia, which greatly limits PDT efficiency, while ambient pathogens also have the opportunity to attach to biorelevant surfaces in medical facilities without light. Here, an antimicrobial film composed of black phosphorus nanosheets (BPSs) and poly (4-pyridonemethylstyrene) endoperoxide (PPMS-EPO) to control the storage and release of ROS reversibly is introduced. BPS, as a biocompatible PS, can produce high singlet oxygen under the irradiation of visible light of 660 nm, which can be stably stored in PPMS-EPO. The ROS can be gradually thermally released in the dark. In vitro antibacterial studies demonstrate that the PPMS-EPO/BPS film exhibits a rapid disinfection ability with antibacterial rate of 99.3% against Escherichia coli and 99.2% against Staphylococcus aureus after 10 min of irradiation. Even without light, the corresponding antibacterial rate reaches 76.5% and 69.7%, respectively. In addition, incorporating PPMS significantly improves the chemical stability of the BPS.

Hesperetin post-treatment prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating PI3K/Akt signaling pathway.

Hesperidin (HES), a citrus fruit extract, has beneficial effects on various ischemia/reperfusion (I/R) models. Here, we investigated the possible positive effect of hesperetin (HPT), an active metabolite of HES, and identified the potential molecular mechanisms involved in cardiomyocytes H/R-induced injury. To construct the cardiomyocyte model of hypoxia/reoxygenation (H/R) injury, cultured neonatal rat cardiomyocytes were subjected to 3h of hypoxia followed by 3h of reoxygenation. Cell viability and apoptosis were detected. The levels of Apoptosis-related proteins and PI3K/Akt proteins were detected by western blot. Our results showed that HPT post-treatment significantly inhibited apoptosis by elevating the expression of Bcl-2, decreasing the expression of Bax and cleaved caspase-3, and diminished the apoptotic cardiomyocytes ratio. Mechanism studies demonstrated that HPT post-treatment up-regulated the expression levels of p-PI3K, and p-Akt. Co-treatment of the cardiomyocytes with the PI3K/Akt-specific inhibitor LY294002 blocked the HPT-induced cardioprotective effects. Taken together, these data suggested that HPT post-treatment prevented cardiomyocytes from H/R injury in vitro most likely through the activation of PI3K/Akt signaling pathway.

A new activated primary tank developed for recovering carbon source and its application.

A novel activated primary tank process (APT) was developed for recovering carbon source by fermentation and elutriation of primary sludge. The effects of solids retention time (SRT), elutriation intensity (G) and return sludge ratio (RSR) on this recovery were evaluated in a pilot scale reactor. Results indicated that SRT significantly influenced carbon source recovery, and mechanical elutriation could promote soluble COD (SCOD) and VFA yields. The optimal conditions of APT were SRT=5d, G=152s(-1) and RSR=10%, SCOD and VFA production were 57.0mg/L and 21.7mg/L. Particulate organic matter in sludge was converted into SCOD and VFAs as fermentative bacteria were significantly enriched in APT. Moreover, the APT process was applied in a wastewater treatment plant to solve the problem of insufficient carbon source. The outcomes demonstrated that influent SCOD of biological tank increased by 31.1%, which improved the efficiency of removing nitrogen and phosphorus.

Resveratrol attenuates hypoxia/reoxygenation­induced Ca2+ overload by inhibiting the Wnt5a/Frizzled­2 pathway in rat H9c2 cells.

Resveratrol is able to protect myocardial cells from ischemia/reperfusion­induced injury. However, the mechanism has yet to be fully elucidated. In the present study, it is reported that resveratrol has a critical role in the control of Ca2+ overload, which is the primary underlying cause of ischemia/reperfusion injury. Hypoxia/reoxygenation (H/R) treatment decreased the cell viability and increased the apoptosis of H9c2 cells, whereas the caspase­3 and intracellular Ca2+ levels were greatly elevated compared with the control group. Treatment of H9c2 cells with resveratrol (5, 15 and 30 µM) reduced caspase­3 expression and cardiomyocyte apoptosis in a dose­dependent manner, and the intracellular Ca2+ overload was also significantly decreased. Furthermore, Frizzled­2 and Wnt5a belong to the non­canonical Wnt/Ca2+ pathway, which have been demonstrated to be responsible for Ca2+ overload, and were thus detected in the present study. The results indicated that both the mRNA and protein expression levels of Frizzled­2 and Wnt5a in H/R­induced H9c2 cells were markedly increased compared with the levels found in normal cells, and treatment with resveratrol (5, 15 and 30 µM) significantly reduced the expression of Frizzled­2 and Wnt5a compared with the H/R group. The results indicated that resveratrol protected myocardial cells from H/R injury by inhibiting the Ca2+ overload through suppression of the Wnt5a/Frizzled­2 pathway.