A dimer-monomer transition captured by the crystal structures of cyanobacterial apo flavodoxin.

In cyanobacteria and algae (but not plants), flavodoxin (Fld) replaces ferredoxin (Fd) under stress conditions to transfer electrons from photosystem I (PSI) to ferredoxin-NADP+ reductase (FNR) during photosynthesis. Fld constitutes a small electron carrier noncovalently bound to flavin mononucleotide (FMN), and also an ideal model for revealing the protein/flavin-binding mechanism because of its relative simplicity compared to other flavoproteins. Here, we report two crystal structures of apo-Fld from Synechococcus sp. PCC 7942, one dimeric structure of 2.09 Å and one monomeric structure of 1.84 Å resolution. Analytical ultracentrifugation showed that in solution, apo-Fld exists both as monomers and dimers. Our dimer structure contains two ligand-binding pockets separated by a distance of 45 Å, much longer than the previous structures of FMN-bound dimers. These results suggested a potential dimer-monomer transition mechanism of cyanobacterial apo-Fld. We further propose that the dimer represents the "standby" state to stabilize itself, while the monomer constitutes the "ready" state to bind FMN. Furthermore, we generated a new docking model of cyanobacterial Fld-FNR complex based on the recently reported cryo-EM structures, and mapped the special interactions between Fld and FNR in detail.

A comparison of Remdesivir versus gold cluster in COVID-19 animal model: A better therapeutic outcome of gold cluster.

While gold compound have been approved for Rheumatoid arthritis treatment as it well suppresses inflammatory cytokines of patients, no such treatment is currently available for COVID-19 treatment in vivo . We firstly disclose gold cluster yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from gold cluster (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication and intrinsically down-regulates NFκB pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 hamsters.

A chlorin-lipid nanovesicle nucleus drug for amplified therapeutic effects of lung cancer by internal radiotherapy combined with the Cerenkov radiation-induced photodynamic therapy.

Traditional photodynamic therapy (PDT) requires external light excitation to produce reactive oxygen species (ROSs) for the treatment of tumors. Due to problems of light penetration, traditional PDT is limited by the location and depth of the tumor. In this study, we rationally designed and constructed a novel strategy to amplify the therapeutic effect of PDT. We prepared a chlorin-lipid nanovesicle based on the conjugates of chlorin e6 (Ce 6) and phospholipids, with the surface conjugating the aptamer for lung cancer targeting, GLT21.T. 131I-labeled bovine serum albumin (131I-BSA) was loaded into the chlorin-lipid nanovesicle cavity (131I-BSA@LCN-Apt). 131I not only plays a role in radiotherapy, but its Cerenkov radiation (CR), as an internal light source, can also stimulate Ce6 to produce ROSs without external light excitation. The in vitro and in vivo therapeutic effects in subcutaneous lung tumor models and orthotopic lung tumor models indicated that 131I-BSA@LCN-Apt produced a powerful anti-tumor effect through synergistic radiotherapy and CR-PDT, which almost caused complete tumor growth regression. After treatment, the survival time of the mice was significantly prolonged. During the treatment, no obvious side effects were found by histopathology of important organs, hematology and biochemistry analysis except the decrease of the white blood cell count (WBC). The study provides a major tool for deep-seated tumors to obtain amplified therapeutic effects by synergistic radiotherapy and CR-PDT without the use of any external light source.

Prodrug-Based Nanoreactors with Tumor-Specific In Situ Activation for Multisynergistic Cancer Therapy.

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based ß-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with ß-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing ß-d-glucose oxidation to form hydrogen peroxide (H2O2) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.

Porous Organic Polymer-Coated Band-Aids for Phototherapy of Bacteria-Induced Wound Infection.

Band-Aids have been widely used for wound care. For most adhesive bandages, however, they have a limited capacity to speed up the wound healing process, which in turn may cause serious wound infections. In this study, antibacterial Band-Aids, combining porphyrin-based porous organic polymers (POPs) with commercial antibiotic-free Band-Aids, are designed. Under white light irradiation, POPs can produce effective photothermal heat, as well as highly reactive oxygen species (ROS), thereby triggering the potent hyperthermia and simultaneous ROS increase on wounds. Additionally, white light is similar to sunlight, which makes POP-based Band-Aids (PBAs) ideal wound dressings for wound disinfection.

Mesoporous Platinum Nanotherapeutics for Combined Chemo-photothermal Cancer Treatment.

Recently, nanoparticles that possess combined use in synergistic therapy, real-time imaging, and spatiotemporally controlled therapies have attracted enormous attention. Herein, we fabricated Doxorubicin (DOX)-loaded and ß-cyclodextrin (ß-CD)-capped mesoporous platinum nanoparticles (MPNPs) (DOX/MPNPs-AD-CD) for combined chemo-photothermal cancer therapy. DOX/MPNPs-AD-CD with high photothermal effect and loading rate could release the anticancer drugs stimulated by acidic tumor microenvironment or near-infrared light. Moreover, acid-degradable MPNPs would release cytotoxic Pt2+, which would enhance the efficiency of chemotherapy. In addition, the inherent photoacoustic and photothermal imaging can effectively guide chemo-photothermal therapy to achieve the desired treatment. Taken together, DOX/MPNPs-AD-CD possess the abilities of combined chemo-photothermal therapy and dual-imaging properties. The studies demonstrated that DOX/MPNPs-AD-CD could effectively inhibit tumor cell growth in vivo and in vitro. Thus, this treatment platform is expected to be one of interest for the clinical treatment of cancers.

An adult case of multiphasic disseminated encephalomyelitis manifesting with optic neuritis.

A 25-year-old woman presented with a fever, headache, vomiting and somnolence. Cranial magnetic resonance imaging (MRI) showed multiple lesions in the cerebellum, brainstem, cerebral cortex and subcortex. Oligoclonal bands were positive in the cerebral spinal fluid (CSF). She experienced a good recovery after steroid treatment. Four months later, she developed right vision loss. Repeated MRI showed multiple cranial lesions different from those involved in the first attack in both size and distribution. An abnormal high signal was also observed in the front and intraorbital regions of the right optic nerve. The patient's vision progressively improved, and she obtained a full recovery following the administration of steroids. A diagnosis of multiphasic disseminated encephalomyelitis manifesting with optic neuritis was made.

S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein.

Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults. Al-though effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular ho-meostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these responses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cell membrane, and restored the disturbed cellular homeostasis, thereby exerting a neu-roprotective effect on hippocampal neurons.