Combination of Hua Shi Bai Du granule (Q-14) and standard care in the treatment of patients with coronavirus disease 2019 (COVID-19): A single-center, open-label, randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of Hua Shi Bai Du Granule (Q-14) plus standard care compared with standard care alone in adults with coronavirus disease (COVID-19). STUDY DESIGN: A single-center, open-label, randomized controlled trial. SETTING: Wuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020. PARTICIPANTS: A total of 204 patients with laboratory-confirmed COVID-19 were randomized into the treatment group and control group, consisting of 102 patients in each group. INTERVENTIONS: In the treatment group, Q-14 was administered at 10 g (granules) twice daily for 14 days, plus standard care. In the control group, patients were provided standard care alone for 14 days. MAIN OUTCOME MEASURE: The primary outcome was the conversion time for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral assay. Adverse events were analyzed in the safety population. RESULTS: Among the 204 patients, 195 were analyzed according to the intention-to-treat principle. A total of 149 patients (71 vs. 78 in the treatment and control groups, respectively) tested negative via the SARS-CoV-2 viral assay. There was no statistical significance in the conversion time between the treatment group and control group (Full analysis set: Median [interquartile range]: 10.00 [9.00-11.00] vs. 10.00 [9.00-11.00]; Mean rank: 67.92 vs. 81.44; P = 0.051). The recovery time for fever was shorter in the treatment group than in the control group. The disappearance rate of symptoms like cough, fatigue, and chest discomfort was significantly higher in the treatment group. In chest computed tomography (CT) examinations, the overall evaluation of chest CT examination after treatment compared with baseline showed that more patients improved in the treatment group. There were no significant differences in the other outcomes. CONCLUSION: The combination of Q-14 and standard care for COVID-19 was useful for the improvement of symptoms (such as fever, cough, fatigue, and chest discomfort), but did not result in a significantly higher probability of negative conversion in the SARS-CoV-2 viral assay. No serious adverse events were observed. TRIAL REGISTRATION: ChiCTR2000030288.

A Gd-doped polydopamine (PDA)-based theranostic nanoplatform as a strong MR/PA dual-modal imaging agent for PTT/PDT synergistic therapy.

Based on widely used photoacoustic imaging (PAI) and photothermal properties of polydopamine (PDA), a multifunctional Gd-PDA-Ce6@Gd-MOF (GPCG) nanosystem with a core-shell structure and strong imaging ability was constructed. Benefitting from the metal-organic framework (MOF) structure, GPCG nanoparticles (NPs) showed enhanced magnetic resonance imaging (MRI) ability with high relaxation rates (r1 = 13.72 mM-1 s-1 and r2 = 216.14 mM-1 s-1). The MRI effect of Gd ions combined with the PAI effect of PDA, giving GPCG NPs a dual-modal imaging ability. The core, mainly composed of PDA and photodynamic photosensitizer chlorin e6 (Ce6), achieved photothermal/photodynamic therapy (PTT/PDT) synergistic performance. Besides, to overcome the unexpected release of Ce6, the MOF shell realized pH-sensitive release and a high local concentration. Through in vivo studies, we concluded that GPCG NPs show a good inhibitory effect on tumor growth. In conclusion, we successfully obtained a GPCG theranostic nanoplatform and paved the way for subsequent design of imaging guided therapeutic nanostructures based on metal-doped PDA.

Efficacy and safety of Chinese herbal medicine versus Lopinavir-Ritonavir in adult patients with coronavirus disease 2019: A non-randomized controlled trial.

BACKGROUND: Treatments for coronavirus disease 2019 (COVID-19) are limited by suboptimal efficacy. METHODS: From January 30, 2020 to March 23, 2020, we conducted a non-randomised controlled trial, in which all adult patients with laboratory-confirmed COVID-19 were assigned to three groups non-randomly and given supportive treatments: Group A, Lopinavir-Ritonavir; Group B, Huashi Baidu Formula (a Chinese medicineformula made by the China Academy of Chinese Medical Sciences to treat COVID-19, which is now in the clinical trial period) and Lopinavir-Ritonavir; and Group C, Huashi Baidu Formula. The use of antibiotics, antiviruses, and corticosteroids was permitted in Group A and B. Traditional Chinese medicine injections were permitted in Group C. The primary outcomes were clinical remission time (interval from admission to the first time the patient tested negatively for novel coronavirus or an obvious improvement was observed from chest CT) and clinical remission rate (number of patients whose clinical time was within 16 days/total number of patients). RESULTS: A total of 60 adult patients with COVID-19 were enrolled at sites in Wuhan, China, and the sample size of each group was 20. In Groups A, B and C, the clinical remission rates were 95.0%%(19/20), 100.0%%(20/20) and 100.0%%(20/20), respectively. Compared with Groups A and B, the clinical remission time of Group C was significantly shorter (5.9 days vs. 10.8 days, p < 0.05; 5.9 days vs. 9.7 days, p < 0.05). There was no significant difference among Groups A, B, and C in terms of the time taken to be released from quarantine. The clinical biochemical indicators and safety indexes showed no significant differences among the three groups. CONCLUSIONS: Our findings suggest that Lopinavir-Ritonavir has some efficacy in the treatment of COVID-19, and the Huashi Baidu Formula might enhance this effect to an extent. In addition, superiority was displayed in the treatment of COVID-19 through a combination of the Huashi Baidu Formula and traditional Chinese medicine injection. In future, well-designed prospective double-blinded randomised control trials are required to confirm our findings.

Bioactive MOFs Based Theranostic Agent for Highly Effective Combination of Multimodal Imaging and Chemo-Phototherapy.

Bioactive metal-organic frameworks (bio-MOFs) built from biofunctional metal ions and linkers show a new strategy to construct multifunctional theranostic platforms. Herein, a bio-MOF is synthetized via the self-assembling of Fe3+ ions and doxorubicin hydrochloride (DOX) molecules. Then, through a stepwise assembly strategy, another bio-MOFs structure consisting of Gd3+ ions and 1,3,5-benzenetricarboxylic acid (H3 BTC) is wrapped on the surfaces of Fe-DOX nanoparticles, followed by adsorbing photosensitizer indocyanine green (ICG). Specifically, the Gd-MOF shell structure can not only act as a contrast agent for magnetic resonance imaging (MRI), but also provides protection for Fe-DOX cores, controlling the release of DOX. The photoacoustic and photothermal imaging (PAI and PTI) methods are successfully introduced to the platform by loading ICG, providing potential applications for multimodal biological imaging. The in vitro and in vivo outcomes indicate that the Fe-DOX@Gd-MOF-ICG nanoplatform exhibits outstanding synergistic antitumor performance via MR/PA/PT imaging guided chemotherapy, photothermal and photodynamic combination therapy. The work may encourage further exploration of bio-MOFs based multifunctional theranostic platforms for multimodal imaging guided compound antitumor therapy, which will open an avenue of MOFs toward biological applications.

A one-pot synthesis of multifunctional Bi2S3 nanoparticles and the construction of core-shell Bi2S3@Ce6-CeO2 nanocomposites for NIR-triggered phototherapy.

As a direct thin band gap n-type semiconductor, bismuth sulfide (Bi2S3) nanomaterials possess great near-infrared (NIR)-triggered photothermal effects, photoacoustic (PA) and computed tomography (CT) imaging properties. Hence, Bi2S3 nanomaterials have become a research focal point in multiple domains, such as the construction of NIR-triggered nanosystems for cancer therapy. In this study, through a simple one-pot synthesis with the assistance of EDTA-2Na, we first obtained monodispersed spherical Bi2S3 of uniform particle sizes with fascinating photothermal and PA/CT imaging properties. Based on this, we introduced the photosensitizer Ce6 with photodynamic property and CeO2 with the O2-evolving characteristic, and thus designed a core-shell structure of the Bi2S3@Ce6-CeO2 nanocomposites (Bi2S3@Ce6-CeO2 NCs). The as-received Bi2S3@Ce6-CeO2 NCs exhibited a remarkable synergetic photothermal and photodynamic therapeutic effect both in vitro and in vivo, demonstrating its promising potential for cancer treatments. In the long term, the multifunctional PA/CT properties of both Bi2S3 NPs and Bi2S3@Ce6-CeO2 NCs in this study also supply a novel Bi2S3-based platform for constructing integrated diagnosis and treatment platforms.

Novel Tumor-Microenvironment-Based Sequential Catalytic Therapy by Fe(II)-Engineered Polydopamine Nanoparticles.

Traditional tumor treatments suffer from severe side effects on account of their invasive process and inefficient outcomes. Featuring a unique physical microenvironment, the tumor microenvironment (TME) provides a new research direction for designing more efficient and safer treatment paradigms. In this study, we fabricated a polydopamine (PDA)-based TME-responsive nanosystem, which successfully integrates glucose degradation, the Fenton reaction, and photothermal therapy for efficient cancer therapy. Through a convenient hydrothermal method, Fe2+-doped Fe(II)-PDA nanoparticles were successfully fabricated, which show an excellent photothermal effect and interesting reactivity for the Fenton reaction. Instead of introducing toxic anticancer agents, natural glucose oxidase (GOD) was grafted on Fe(II)-PDA, forming a cascade catalytic nanomedicine for a specific response to the glucose in TME. GOD grafted on Fe(II)-PDA-GOD is ought to catalyze abundant glucose in TME into gluconic acid and H2O2. The concomitant generation of H2O2 can enhance the efficiency of the sequential Fenton reaction, producing abundant hydroxyl radicals (•OH) for cancer therapy. Besides, the overconsumption of intratumoral glucose also could inhibit tumor growth by reducing the energy supply. Taken together, the in vitro and in vivo antitumor studies of such TME-based Fe(II)-PDA-GOD nanosystems displayed a favorable synergistic potency of glucose degradation, the Fenton reaction, and photothermal therapy against tumor growth. Our design expands the biological application of multifunctional PDA while providing novel strategies toward effective antitumor treatment with minimal side effects.

Ecdysterones from Rhaponticum carthamoides (Willd.) Iljin reduce hippocampal excitotoxic cell loss and upregulate mTOR signaling in rats.

Glutamate-induced excitotoxicity is a key pathological mechanism in many neurological disease states. Ecdysterones derived from Rhaponticum carthamoides (Willd.) Iljin (RCI) have been shown to alleviate glutamate-induced neuronal damage; although their mechanism of action is unclear, some data suggest that they enhance signaling in the mechanistic target of rapamycin (mTOR) signaling pathway. This study sought to elucidate the mechanisms underlying ecdysterone-mediated neuroprotection. We used in silico target prediction and simulation methods to identify putative ecdysterone binding targets, and to specifically identify those that represent nodes where several neurodegenerative diseases converge. We then used histological analyses in a rat hippocampal excitotoxicity model to test the effectiveness of ecdysterones in vivo. We found that RCI-derived ecdysterones should bind to glutamatergic NMDA-type receptors (NMDARs); specifically, in vivo modeling showed binding to the GRIN2B subunit of NMDARs, which was found also to be a node of convergence in several neurodegenerative disease pathways. Computerized network construction by using pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed putative links between GRIN2B and mTOR pathway elements including phosphoinositide-3kinase (PI3K), mTOR, and protein kinase C (PKC); these elements are associated with neuronal survival. Brain tissue western blots of ecdysterone-treated rats showed upregulated PI3K, Akt, mTOR, and phosphorylated Akt and mTOR, and down regulated GRIN2B and the apoptotic enzyme cleaved caspase-3. Ecdysterone treatment also prevented glutamate-induced rat hippocampal cell loss. In summary, RCI-derived ecdysterones appear to prevent glutamatergic excitotoxicity by increasing mTOR/Akt/PI3K signaling activity.

PPy@MIL-100 Nanoparticles as a pH- and Near-IR-Irradiation-Responsive Drug Carrier for Simultaneous Photothermal Therapy and Chemotherapy of Cancer Cells.

A medical nanoplatform with small size, low cost, biocompatibility, good biodegradability, and, in particular, multifunctionality has attracted much attention in the exploration of novel therapeutic methodologies. As an emerging material of self-assembled porous structure, metal-organic frameworks (MOFs) have high expectations because of their special properties compared to traditional porous materials. Therefore, integration of MOFs and functional materials is leading to the creation of new multifunctional composites/hybrids. Photothermal therapy (PTT), using near-IR (NIR) laser-absorbing nanomaterials as PTT agents, has shown encouraging therapeutic effects to photothermally ablate tumors. However, the most of widely used PTT agents are inorganic materials and nonbiodegradable. Herein, uniform polypyrrole (PPy) nanoparticles (NPs) with good biodegradability were synthesized by a microemulsion method. The PPy NPs were further coated with the mesoporous iron-based MOF structure MIL-100 by interaction between PPy NPs and MIL-100 precursors at room temperature. As a multifunctional nanoplatform, an anticancer drug could easily be loaded into the mesopores of the MIL-100 shell. The PPy core, as an organic photothermal agent, is able to photothermally ablate cancer cells and improve the efficacy of chemotherapy under NIR irradiation. The composites showed an outstanding in vivo synergistic anticancer capacity. Our work could encourage further study in the construction of a synergetic system using MOFs and organic PTT agents.