Broad-spectrum antiviral effect of MoringaA-loaded exosomes against IAV by mediating the GCN5-TFEB-autolysosome pathway.

Influenza virus-induced viral pneumonia is a major threat to human health, and specific therapeutic agents for viral pneumonia are still lacking. MoringaA (MA) is an anti-influenza virus active compound isolated from Moringa seeds, which can inhibit influenza virus by activating the TFEB-autophagic lysosomal pathway in host cells. In this study, we obtained exosomes from M2-type macrophages and encapsulated and delivered MA (MA-Exos), and we investigated the efficacy of MA-Exos in antiviral and viral pneumonia in vivo and in vitro, respectively. In addition, we provided insights into the mechanism by which MA-Exos regulates TFEB-lysosomal autophagy by RNA sequencing. The MA-Exos showed broad-spectrum inhibition of IAV, and significant promotion of the autophagic lysosomal pathway. Meanwhile, we found that GCN5 gene and protein were significantly down-regulated in IAV-infected cells after MA-Exos intervention, indicating its blocking the acetylation of TFEB by GCN5. In addition, MA-Exos also significantly promoted autophagy in lung tissue cells of mice with viral pneumonia. MA-Exos can inhibit and clear influenza virus by mediating the TFEB-autophagy lysosomal pathway by a mechanism related to the down-regulation of histone acetyltransferase GCN5. Our study provides a strategy for targeting MA-Exos for the treatment of viral pneumonia from both antiviral and virus-induced inflammation inhibition pathways.

Nano-Characterization, Composition Analysis, and Anti-Inflammatory Activity of American-Ginseng-Derived Vesicle-like Nanoparticles.

Medicinal plant-derived vesicle-like nanoparticles can carry chemical components and exert intercellular activity due to the encapsulation of nanostructures. American ginseng is well known as a traditional herb and is commonly used in clinical decoctions. However, the nano-characteristics and chemical composition of American-ginseng-derived vesicle-like nanoparticles (AGVNs) in decoctions are unclear. In this study, the gradient centrifugation method was used to extract and isolate AGVNs. A metabolomic method based on high-resolution mass spectrometry was established to analyze small molecules loaded in AGVNs. Zebrafish and RAW264.7 cells were employed to investigate the anti-inflammatory effects of AGVNs. The results showed that the particle size of AGVNs was generally 243.6 nm, and the zeta potential was -14.5 mV. AGVNs were found to contain 26 ginsenosides (14 protopanaxadiols, 11 protopanaxatriols, and 1 oleanolic acid). Ginsenoside Rb1 and malonyl-ginsenoside Rb1 tended to be enriched in AGVNs. Moreover, AGVNs were found to exert anti-inflammatory effects by reducing macrophage migration in zebrafish and regulating inflammatory factor (NO, TNF-α, IL-6, IL-10) secretion in RAW 264.7 cells. The characterization and analysis of AGVNs provide references and data that support the development of nanoscale anti-inflammatory substances from medicinal plants.

The emerging role of PANoptosis in cancer treatment.

Programmed cell death (PCD) is a key mechanism for the study of anticancer drugs and has a significant impact on the development and management of cancer. A growing amount of data indicates that different kinds of PCD, particularly pyroptosis, apoptosis, and necroptosis, interact closely. Recent research has revealed the existence of the distinct inflammatory PCD modality known as PANoptosis, which is controlled by complex PANoptosome complexes built by combining elements from different PCD pathways. No single PCD route is sufficient to explain all of the physiologic effects seen in PANoptosis. Numerous studies have demonstrated that PANoptosis can successfully stop cancer cells from growing, proliferating, and developing drug resistance. As a result, it has changed the focus of targeted anticancer therapy. In this review, we outlined the molecular processes of PANoptosis activation and modulation as well as the mechanisms of innate immune cell death. In order to provide a theoretical foundation for the development of drugs targeting PANoptosis as an anti-cancer target, we also highlight the PANoptosomes discovered to date and give an overview of the implications of PANoptosis in cancer treatment.

Gold Nanoparticles Coated with SH-PEG-NH2 and Loaded with Ziyuglycoside I for Promoting Autophagy in Hematopoietic Stem Cells.

Introduction: Radiotherapy and chemotherapy are the fundamental causes of myelosuppression in cancer patients, which usually induce a serious hematopoietic system toxicity, causing the hemocytes and immunity decline of patients. Ziyuglycoside I (ZgI), an active ingredient isolated from traditional Chinese medicine Sanguisorba officinalis L, has been demonstrated to increase the leucocytes and protect hematopoietic stem cells, which is related to its promotion of autophagy in hematopoietic stem cells. Methods: In the present study, we formulated the SH-PEG-NH2-coated gold nanoparticles loading ZgI (ZgI-AuNPs) with a enhanced autophagy promotion in hematopoietic stem cells. ZgI-AuNPs were prepared by HAuCl4-sodium citrate reduction method, and the synthesis of ZgI-AuNPs was validated by XRD, FT-IR, DSC, and TEM findings. Furthermore, the drug loading rate and the release of ZgI were evaluated, and the ZgI-AuNPs' effects on autophagy and immunofluorescence staining for LC3B were tested. Finally, the effect of ZgI-AuNPs on the autophagy and hematopoietic ability of HSCs in vivo was also carried out. Results: The prepared ZgI-AuNPs have an irregular cubic crystal structure by TEM observation, and the average particle size was 340 ± 16.5 nm determined by DLS. The XRD, FT-IR and DSC detection showed that the ZgI had been well loaded in AuNPs, and the AuNPs can load the ZgI at a content of 160.63 ± 1.35 µg·mg-1. Meanwhile, the AuNPs can reduce the drug release rate of ZgI. Importantly, the ZgI-AuNPs enhanced autophagy of HSCs both in vitro and in vivo. At the same time, the gold nanoparticles enhance the hematopoietic effect of ZgI on mice HSCs. Conclusion: Our research suggests that SH-PEG-NH2-coated gold nanoparticles loading ZgI has potential application in myelosuppression therapy.

The crosstalk between classic cell signaling pathways, non-coding RNAs and ferroptosis in drug resistance of tumors.

Ferroptosis is an iron-dependent oxidative cell death characterized by the lethal accumulation of lipid-based reactive oxygen species (ROS), which is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis be critical in regulating the growth and drug resistance of tumors, thus providing potential targets for cancer therapy. The development of resistance to cancer therapy remains a major challenge. Ferroptosis is associated with cancer drug resistance and inducing ferroptosis has been demonstrated to reverse drug resistance. This review focuses on a detailed account of the interplay between ferroptosis and related signaling pathways, including the Hippo signaling pathway, Keap1-Nrf2-ARE signaling pathway, Autophagy, and non-coding RNAs, which will shed light on developing the therapeutic role of regulating ferroptosis in reversing the resistance of cancer.

Recent Advances in Antiviral Activities of Triterpenoids.

Triterpenoids, important secondary plant metabolites made up of six isoprene units, are found widely in higher plants and are studied for their structural variety and wide range of bioactivities, including antiviral, antioxidant, anticancer, and anti-inflammatory properties. Numerous studies have demonstrated that different triterpenoids have the potential to behave as potential antiviral agents. The antiviral activities of triterpenoids and their derivatives are summarized in this review, with examples of oleanane, ursane, lupane, dammarane, lanostane, and cycloartane triterpenoids. We concentrated on the tetracyclic and pentacyclic triterpenoids in particular. Furthermore, the particular viral types and possible methods, such as anti-human immunodeficiency virus (HIV), anti-influenza virus, and anti-hepatitis virus, are presented in this article. This review gives an overview and a discussion of triterpenoids as potential antiviral agents.

Review of lignans from 2019 to 2021: Newly reported compounds, diverse activities, structure-activity relationships and clinical applications.

Lignans, with various biological activities, such as antitumor, antioxidant, antibacterial, and antiviral activities, are widely distributed in nature and mainly exist in the xylem of plants. In this paper, we summarized the structures and bioactivities of lignans reported in recent years (2019-2021) from five parts, including (1) a summary and classification of newly reported compounds; (2) the pharmacological activities of lignans; (3) molecular resources and activity distribution; (4) the structure-activity relationships; and (5) the clinical application of lignans. This review covers all undescribed compounds that were reported within the covered period of time and all bioactivity data about previously isolated lignans. The distribution of lignans in different plants and families is visualized, which improves the efficiency of searching for specific molecules. The diverse activities of different types of lignans provide an important reference for the rapid screening of these compounds. Discussion about the structure-activity relationships of lignans provides a direction for the structural modification of skeleton molecules. Combined with the clinical application of such molecules, this work will provide a valuable reference for pharmaceutical chemists.

The crosstalk between the caspase family and the cGAS‒STING signaling pathway.

Edited by Jiarui Wu Cytosolic nucleic acid sensors are critical for sensing nucleic acids and initiating innate immunity during microbial infections and/or cell death. Over the last decade, several key studies have characterized the conserved mechanism of cyclic guanosine monophosphate‒adenosine monophosphate synthase (cGAS) and the downstream signaling adaptor stimulator of interferon genes (STING) initiating the innate immune signaling pathways. Aside from its primary involvement in microbial infections and inflammatory diseases, there is growing interest in the alternate roles of cGAS‒STING-mediated signaling. Caspase family members are powerful functional proteins that respond to cellular stress, including cell death signals, inflammation, and innate immunity. Recent studies have uncovered how the caspase family cooperates with the cGAS‒STING signaling pathway. Most caspase family members negatively regulate the cGAS‒STING signaling pathway. In turn, some caspase family members can also be modulated by cGAS‒STING. This review gives a detailed account of the interplay between the caspase family and the cGAS‒STING signaling pathway, which will shed light on developing novel therapeutics targeting the caspase family and cGAS‒STING signaling in antiviral innate immunity, cancer, inflammatory, and autoimmunity.

Probiotic Supplements: Their Strategies in the Therapeutic and Prophylactic of Human Life-Threatening Diseases.

Chronic diseases and viral infections have threatened human life over the ages and constitute the main reason for increasing death globally. The rising burden of these diseases extends to negatively affecting the economy and trading globally, as well as daily life, which requires inexpensive, novel, and safe therapeutics. Therefore, scientists have paid close attention to probiotics as safe remedies to combat these morbidities owing to their health benefits and biotherapeutic effects. Probiotics have been broadly adopted as functional foods, nutraceuticals, and food supplements to improve human health and prevent some morbidity. Intriguingly, recent research indicates that probiotics are a promising solution for treating and prophylactic against certain dangerous diseases. Probiotics could also be associated with their essential role in animating the immune system to fight COVID-19 infection. This comprehensive review concentrates on the newest literature on probiotics and their metabolism in treating life-threatening diseases, including immune disorders, pathogens, inflammatory and allergic diseases, cancer, cardiovascular disease, gastrointestinal dysfunctions, and COVID-19 infection. The recent information in this report will particularly furnish a platform for emerging novel probiotics-based therapeutics as cheap and safe, encouraging researchers and stakeholders to develop innovative treatments based on probiotics to prevent and treat chronic and viral diseases.

TPGS-Modified Long-Circulating Liposomes Loading Ziyuglycoside I for Enhanced Therapy of Myelosuppression.

BACKGROUND: Ziyuglycoside I (ZgI), an active ingredient isolated from traditional Chinese medicine Sanguisorba officinalis L, has been demonstrated to increase the leucocytes and protect hematopoietic stem cells. However, the poor solubility and a short half-life of ZgI limit its bioavailability and efficacy. The D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) has been widely used to increase the solubility, improve the encapsulation rate, and extend the half-life of drugs. METHODS: Here, we formulated the TPGS-modified long-circulating liposomes loading ZgI with a sustained drug release and enhanced therapy for myelosuppression. ZgI-TPGS-liposomes were manufactured using a thin-film hydration technique, followed by characterizations of physicochemical properties, including the particle size, zeta potential, TEM, SEM, FTIR, XRD, stability, drug loading (DL), encapsulation efficiency (EE). The in vitro and in vivo delivery efficiency were further evaluated by cellular uptake, in vitro drug release and in vivo pharmacokinetics. Finally, therapeutic effect on myelosuppression was investigated. RESULTS: The ZgI-TPGS-liposomes had an particle size of 97.89 ± 1.42 nm and ZP of -28.65 ± 0.16 mV. It exhibited DL of 9.06 ± 0.76% and EE of 92.34 ± 3.83%, along with excellent storage stability, cellular uptake and sustained drug release to free ZgI and liposomes without TPGS. Additionally, the TPGS modified liposomes significantly enhanced the therapeutic effect of ZgI on CTX induced myelosuppression, which can be confirmed in the apoptosis inhibition and cell viability promotion of CTX injured HSPC-1 cells. Also, the mice in vivo pharmacodynamics demonstrated that TPGS liposomes promoted ZgI increasing the numbers of leucocytes and neutrophils in myelosuppression mice induced by CTX. CONCLUSION: Our research suggest that TPGS-modified long-circulating liposomes loading ziyuglycoside I has potential application in myelosuppression therapy.

Peroxide- and transition metal-free electrochemical synthesis of α,ß-epoxy ketones.

A novel electrochemical method for the synthesis of α,ß-epoxy ketones is reported. With KI as the redox mediator, methyl ketones reacted with aldehydes under peroxide- and transition metal-free electrolytic conditions and afforded α,ß-epoxy ketones in one pot (36 examples, 52-90% yield). This safe and environmental-friendly method has a broad substrate scope and can readily provide a variety of α,ß-epoxy ketones in gram-scales for evaluation of their anti-cancer activities.

Formulation and evaluation of a topical liposomal gel containing a combination of zedoary turmeric oil and tretinoin for psoriasis activity.

This study was to develop a combination of zedoary turmeric oil (ZTO) and tretinoin (TRE)-loaded liposomal gel as a topical drug delivery system. We used a combination of single-factor experiment and orthogonal experiment to systematically optimize encapsulation process of the compound liposomes. The optimized liposome vesicles were incorporated into Carbopol gel matrix and studied by continuous in vitro (skin penetration and retention) and in vivo (anti-psoriatic activity using mouse vaginal model and mouse tail model) experiments. The optimized liposomes had an entrapment efficiency (EE) of ZTO was (64.63 ± 1.00)%, EE of TRE was (90.33 ± 0.72)%, drug loading (DL) of ZTO was (9.09 ± 0.14)%, DL of TRE was (1.43 ± 0.02)%, particle size of 257.41 ± 7.58 nm, polydispersity index (PDI) of 0.10 ± 0.04 and zeta potential of -38.77 ± 0.81 mV. Transmission electron microscopy showed liposomes had a regular spherical surface. After 1-month storage at (4 ± 2)°C, the optimized liposome preparations maintained its stability. In vitro study indicated that liposome formulations could significantly prolong the penetration of drugs into the hair follicles of mice and keep more drugs in the skin compared with conventional gel formulations. In vivo study showed that liposomal gel was more effective than conventional gel in treating psoriasis and had a significant dose-dependent effect on psoriasis. In summary, liposomal gel is expected to be an ideal carrier for topical drug delivery systems of ZTO and TRE.

Development and In Vivo Evaluation of Ziyuglycoside I-Loaded Self-Microemulsifying Formulation for Activity of Increasing Leukocyte.

Ziyuglycoside I (ZgI), a major effective ingredient of Sanguisorba officinalis L, has shown good activity in increasing leukocyte of myelosuppression mice. However, oral ZgI therapy has been deterred by poor bioavailability because of its low aqueous solubility and permeability. Our study was to develop ZgI-loaded self-microemulsifying drug delivery system (SMEDDS) and evaluate its intestinal absorption, and pharmacokinetic and pharmacodynamic activity for increasing leukocyte. The formulation was designed and optimized by measuring the equilibrium solubility of ZgI in different vehicles and the pseudoternary phase diagram. Further, morphology, particle size, stability, in vitro release, in situ single-pass intestinal perfusion (SPIP), in vivo activity, and in vivo pharmacokinetic (PK) of ZgI-SMEDDS were charactered or studied. Optimized formulations for in vitro dissolution were Obleique CC497, Tween-20, and Transcutol HP with a proportion of 0.25/0.45/0.30 via D-optimal mixture design. Results showed that the solubility of ZgI was enhanced up to 23.93 mg/g and its average particle size was 207.92 ± 2.13 nm. The release of ZgI had been greatly improved by the SMEDDS. In SPIP, the intestinal absorption of SMEDDS was much better than plain ZgI. In PK, we found the oral bioavailability of ZgI-SMEDDS was 6.94-fold higher absolute bioavailability (21.94 ± 4.67) % than ZgI (3.16 ± 0.89) %. The most important was that the mice WBC of ZgI-SMEDDS group was significantly higher than that of the ZgI group. Our study suggested that SMEDDS could increase the solubility of ZgI, which was beneficial to improve oral bioavailability and enhance biological activity.