Isoquercitrin alleviates OGD/R-induced oxidative stress and impaired mitochondrial biogenesis in SH-SY5Y cells via the NRF1/TFAM pathway.

Isoquercitrin (ISO) is a traditional Chinese medicine extract, that has been found to possess potent neuroprotective properties. However, its precise role in the context of ischemic stroke (IS) remains to be fully elucidated. We constructed an in vitro model of IS induced by OGD/R in SH-SY5Y cells. Cell viability, the levels of oxidative stress-related indicators (8-OHDG, MDA, SOD, GSH, and GSH-Px), ROS, and mitochondrial membrane potential were measured by using detection kits. The protein levels of GPX1, SOD, Cytc were measured. The mRNA levels of mitochondrial biogenesis-related indicators (Cytb, CO1, ND2, ND5, and ND6), and mtDNA copy number were measured by RT-qPCR. ATP levels were measured. Molecular docking between ISO and NRF1, and Co-IP assay for NRF1 and TFAM interaction were performed. Expression of NRF1 and TFAM was evaluated. ISO treatment reversed the detrimental effects of OGD/R on cell viability, attenuated the elevation of oxidative stress markers, restored antioxidant levels, and alleviated the impairment of mitochondrial biogenesis in SH-SY5Y cells. ISO interacted with NRF1 and increased its expression along with TFAM. Silencing NRF1 reversed the protective effects of ISO, suggesting its involvement in mediating the neuroprotective effects of ISO. ISO alleviates oxidative stress and mitochondrial biogenesis damage induced by OGD/R in SH-SY5Y cells by upregulating the NRF1/TFAM pathway.

Characteristics and degradation mechanisms of polychlorinated naphthalenes in surface soil in Yangtze River Delta, China.

Both thermal and environmental processes are significant factors influencing the existing characteristics, e.g., congener distributions, and existing levels, of polychlorinated naphthalenes (PCNs) in the environment. Soil plays an important role in the life cycle of PCNs, but degradation of PCNs in soils has never been reported. In this study, we collected surface soil samples from 13 cities in the Yangtze River Delta, which is one of the most crowded areas of China and analyzed the samples for 75 PCNs. The long-range transportation from polluted areas was the major source for PCNs in remote areas, but the PCN profiles in remote areas reported in our previous studies were different from those in human settlement in this study, indicating there is a transformation of PCNs after emissions from anthropogenic activities. Two experiments were then designed to reveal the degradation mechanisms, including influencing factors, products, and pathways, of PCNs in surface soils. Based on the experiments, we found that the major factor driving the losses of PCNs in surface soils was volatilization, followed by photo irradiation and microbial metabolism. Under photo-irradiation, the PCN structures would be destroyed through a process of dechlorination followed by oxidation. In addition, the dechlorination pathways of PCNs have been established and found to be significantly influenced by the structure-related parameters.

Photocatalytic manipulation of Ca2+ signaling for regulating cellular and animal behaviors via MOF-enabled H2O2 generation.

The in situ generation of H2O2 in cells in response to external stimulation has exceptional advantages in modulating intracellular Ca2+ dynamics, including high controllability and biological safety, but has been rarely explored. Here, we develop photocatalyst-based metal-organic frameworks (DCSA-MOFs) to modulate Ca2+ responses in cells, multicellular spheroids, and organs. By virtue of the efficient photocatalytic oxygen reduction to H2O2 without sacrificial agents, photoexcited DCSA-MOFs can rapidly trigger Ca2+ outflow from the endoplasmic reticulum with single-cell precision in a repeatable and controllable manner, enabling the propagation of intercellular Ca2+ waves (ICW) over long distances in two-dimensional and three-dimensional cell cultures. After photoexcitation, ICWs induced by DCSA-MOFs can activate neural activities in the optical tectum of tadpoles and thighs of spinal frogs, eliciting the corresponding motor behaviors. Our study offers a versatile optical nongenetic modulation technique that enables remote, repeatable, and controlled manipulation of cellular and animal behaviors.

Communication molecules (ncRNAs) mediate tumor-associated macrophage polarization and tumor progression.

Non-coding RNAs play important roles in tumor cells and macrophages and participate in their communication as messengers. Non-coding RNAs have an impact in tumor cell proliferation, migration, and apoptosis, and they also regulate the differentiation and regulation of immune cells. In macrophages, they stimulate the polarization of macrophages into M1 or M2 by regulating proteins related to signaling pathways; in tumor cells, non-coding RNAs can enter macrophages through exosomes and affect the latter polarization. The polarization of macrophages further regulates the biological functions of cancer cells. The direction of macrophage polarization determines tumor progression, angiogenesis and drug resistance. This often creates a feedback loop. Non-coding RNAs act as bridges between tumor cells and macrophages to regulate the balance of the tumor microenvironment. We reviewed the signaling pathways related to macrophage polarization and the regulatory mechanisms of non-coding RNA in tumor-associated macrophages M1 and M2, and discussed the potential applications and prospects of exosome engineering.

Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening.

Hand, foot, and mouth disease (HFMD) is a common pediatric illness mainly caused by enteroviruses, which are important human pathogens. Currently, there are no available antiviral agents for the therapy of enterovirus infection. In this study, an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed. Using this screening system, we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, exhibits potential inhibitory effects against various enteroviruses that cause HFMD, such as EV-A71, CV-A10, CV-B3 and CV-A16. Further investigations revealed that FAN targets the early stage of the enterovirus life cycle. Through the selection of FAN-resistant EV-A71 viruses, we demonstrated that the VP1 protein could be a potential target of FAN, as two mutations in VP1 (E145G and V258I) resulted in viral resistance to FAN. Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

A Chimeric Classical Insect-Specific Flavivirus Provides Complete Protection Against West Nile Virus Lethal Challenge in Mice.

West Nile virus (WNV), an arthropod-borne flavivirus, can cause severe symptoms, including encephalitis, and death, posing a threat to public health and the economy. However, there is still no approved treatment or vaccine available for humans. Here, we developed a novel vaccine platform based on a classical insect-specific flavivirus (cISF) YN15-283-02, which was derived from Culicoides. The cISF-WNV chimera was constructed by replacing prME structural genes of the infectious YN15-283-02 cDNA clone with those of WNV and successfully rescued in Aedes albopictus cells. cISF-WNV was nonreplicable in vertebrate cells and nonpathogenic in type I interferon receptor (IFNAR)-deficient mice. A single-dose immunization of cISF-WNV elicited considerable Th1-biased antibody responses in C57BL/6 mice, which was sufficient to offer complete protection against lethal WNV challenge with no symptoms. Our studies demonstrated the potential of the insect-specific cISF-WNV as a prophylactic vaccine candidate to prevent infection with WNV.

A Comparative Visual Analytics Framework for Evaluating Evolutionary Processes in Multi-Objective Optimization.

Evolutionary multi-objective optimization (EMO) algorithms have been demonstrated to be effective in solving multi-criteria decision-making problems. In real-world applications, analysts often employ several algorithms concurrently and compare their solution sets to gain insight into the characteristics of different algorithms and explore a broader range of feasible solutions. However, EMO algorithms are typically treated as black boxes, leading to difficulties in performing detailed analysis and comparisons between the internal evolutionary processes. Inspired by the successful application of visual analytics tools in explainable AI, we argue that interactive visualization can significantly enhance the comparative analysis between multiple EMO algorithms. In this paper, we present a visual analytics framework that enables the exploration and comparison of evolutionary processes in EMO algorithms. Guided by a literature review and expert interviews, the proposed framework addresses various analytical tasks and establishes a multi-faceted visualization design to support the comparative analysis of intermediate generations in the evolution as well as solution sets. We demonstrate the effectiveness of our framework through case studies on benchmarking and real-world multi-objective optimization problems to elucidate how analysts can leverage our framework to inspect and compare diverse algorithms.

Target Analysis of Polychlorinated Naphthalenes and Nontarget Screening of Organic Chemicals in Bovine Milk, Infant Formula, and Adult Milk Powder by High-Resolution Mass Spectrometry.

Infant formula is intended as an effective substitute for breast milk but is the main source of polychlorinated naphthalenes (PCNs) to nonbreastfed infants. We performed target and nontarget analyses to determine PCNs and identify other organic contaminants in infant formula. The mean PCN concentrations in infant formula, milk powder, and bovine milk were 106.1, 88.8, and 78.2 µg kg-1 of dry weight, respectively. The PCN congener profiles indicated that thermal processes and raw materials were probably the main sources of PCNs in infant formula. A health risk assessment indicated that PCNs in infant formula do not pose health risks to infants. Using gas chromatography-Orbitrap mass spectrometry, 352, 372, and 161 organic chemicals were identified in the infant formula, milk powder, and bovine milk samples, respectively. Phthalate esters were detected in all four plastic-packed milk powder samples. The results indicated milk becomes more contaminated with organic chemicals during manufacturing, processing, and packaging.

Mechanism for Improved Curie Temperature and Magnetic Entropy Change in Sm-Doped Fe88Zr8B4 Amorphous Alloys.

In the present work, Fe88Zr8-xSmxB4 (x = 2, 4) amorphous alloys (AAs) were successfully synthesized into the shape of 40-micrometer-thick ribbons and their magnetic properties were measured. The Fe88Zr8-xSmxB4 (x = 2, 4) AAs exhibited a rather high maximum magnetic entropy change (-ΔSmpeak): ~3.53 J/(K × kg) near 317 K for x = 2 and ~3.79 J/(K × kg) near 348 K for x = 4 under 5 T. The effects of a Sm substitution for Zr on the Curie temperature (Tc) and -ΔSmpeak were studied and compared to those of Nd and Pr substitutions, for the purpose of revealing the mechanism involved in more detail.

Newcastle Disease Virus (NDV)-based vaccine candidate against SARS-CoV-2 Omicron by intranasal immunization.

Despite global vaccination efforts, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and spread globally. Currently, the development of affordable vaccine against Omicron variant of concern (VOC) is necessary. Here, we assessed the safety and immunogenicity of a SARS-CoV-2 vaccine consisting of a live Newcastle disease virus vector expressing the spike (S) protein of Omicron BA.1 administrated intranasally (IN) or intramuscularly (IM) in Golden Syrian hamster model. Immunogenicity studies showed that the prime-boost regimen elicited high antibody titers and the modified S antigen (Sm-F) could induce robust antibody response in low dosage immunization through IN route. Sera of the immunized hamsters provided effective cross-neutralizing activity against different Omicron variants, the prototype and delta strains of SARS-CoV-2. Moreover, the vaccine could provide complete immunoprotection in hamsters against the Omicron BA.1 challenge by either intranasal or intramuscular immunization. Overall, our study provides an alternative nasal vaccine against the SARS-CoV-2 Omicron variants.

Tumor-derived CircRNA_102191 promotes gastric cancer and facilitates M2 macrophage polarization.

BACKGROUND: Gastric cancer is a common malignant tumor of the digestive tract and the fourth leading cause of death from cancer-related diseases. In recent years, many studies have found that circular RNAs play an important role in cancer. Tumor-associated macrophages (TAMs) are also critical for tumor progression. OBJECTIVE: This study examined the role of circRNA_102191 in gastric cancer progression. METHODS: The relative mRNA levels were determined by qRT-PCR. Western blotting and ELISA were used to detect the protein levels. In vitro proliferation was assessed using CCK8 and clonogenic assays. The migration and invasion of cell lines were assessed by transwell-based assays. The interactions between molecules were detected using a luciferase reporter assay. M0 macrophages were induced with PMA. M1 macrophages were induced with LPS and IFN-γ, and M2 macrophages were induced with IL-4. RESULTS: The expression of circRNA_102191 was enhanced significantly in gastric cancer cell lines and clinical tumor tissues. CircRNA_102191 promotes gastric cancer cell progression by regulating miR-493-3p and its downstream target gene XPR1. CircRNA_102191 can enhance the EMT process of gastric cancer cells by promoting the M2 polarization of macrophages. CONCLUSION: CircRNA_102191 promotes the biological function of gastric cancer cells by regulating the miR-493-3p/XPR1 axis and M2 macrophage polarization.

Oridonin inhibits SARS-CoV-2 replication by targeting viral proteinase and polymerase.

COVID-19 has become a global public health crisis since its outbreak in China in December 2019. Currently there are few clinically effective drugs to combat SARS-CoV-2 infection. The main protein (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 are involved in the viral replication, and might be prospective targets for anti-coronavirus drug development. Here, we investigated the antiviral activity of oridonin, a natural small-molecule compound, against SARS-CoV-2 infection in vitro. The time-of-addition analysis showed that oridonin efficiently inhibited SARS-CoV-2 infection by interfering with the genome replication at the post-entry stage. Mechanistically, the inhibition of viral replication by oridonin depends on the oxidation activity of α, ß-unsaturated carbonyl. Further experiments showed that oridonin not only effectively inhibited SARS-CoV-2 Mpro activity, but also had some inhibitory effects on PLpro-mediated deubiquitinating and viral polymerase-catalyzed RNA elongation activities at high concentrations. In particular, oridonin could inhibit the bat SARS-like CoV and the newly emerged SARS-CoV-2 omicron variants (BA.1 and BA.2), which highlights its potential as a pan-coronavirus antiviral agent. Overall, our data provide strong evidence that oridonin is an efficient antiviral agent against SARS-CoV-2 infection.

Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2.

Niclosamide, an oral anthelmintic drug, could inhibit SARS-CoV-2 virus replication through autophagy induction, but high cytotoxicity and poor oral bioavailability limited its application. Twenty-three niclosamide analogs were designed and synthesized, of which compound 21 was found to exhibit the best anti-SARS-CoV-2 efficacy (EC50 = 1.00 µM for 24 h), lower cytotoxicity (CC50 = 4.73 µM for 48 h), better pharmacokinetic, and it was also well tolerated in the sub-acute toxicity study in mice. To further improve the pharmacokinetics of 21, three prodrugs have been synthesized. The pharmacokinetics of 24 indicates its potential for further research (AUClast was 3-fold of compound 21). Western blot assay indicated that compound 21 could down-regulate SKP2 expression and increase BECN1 levels in Vero-E6 cells, indicating the antiviral mechanism of 21 was related to modulating the autophagy processes in host cells.

PF-D-Trimer, a protective SARS-CoV-2 subunit vaccine: immunogenicity and application.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and continues to have a significant impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, which is primarily responsible for the host immune response upon infection. Here we present the preclinical studies of a broadly protective SARS-CoV-2 subunit vaccine developed from our trimer domain platform using the Delta spike protein, from antigen design through purification, vaccine evaluation and manufacturability. The pre-fusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. Immunogenicity studies have shown that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous viral challenge. Neutralizing antibodies induced by this vaccine show cross-reactivity against the ancestral WA1, Delta and several Omicrons, including BA.5.2. The formulated PF-D Trimer is stable for up to six months without refrigeration. The Trimer Domain platform was proven to be a key technology in the rapid production of PF-D-Trimer vaccine and may be crucial to accelerate the development and accessibility of updated versions of SARS-CoV-2 vaccines.

Self-Healing Supramolecular Hydrogels with Antibacterial Abilities for Wound Healing.

Wound healing due to skin defects is a growing clinical concern. Especially when infection occurs, it not only leads to impair healing of the wound but even leads to the occurrence of death. In this study, a self-healing supramolecular hydrogel with antibacterial abilities was developed for wound healing. The supramolecular hydrogels inherited excellent self-healing and mechanical properties are produced by the polymerization of N-acryloyl glycinamide monomers which carries a lot of amides. In addition, excellent antibacterial properties are obtained by integrating silver nanoparticles (Ag NPs) into the hydrogels. The resultant hydrogel has a demonstrated ability in superior mechanical properties, including stretchability and self-healing. Also, the good biocompatibility and antibacterial ability have been proven in hydrogels. Besides, the prepared hydrogels were employed as wound dressings to treat skin wounds of animals. It was found that the hydrogels could significantly promote wound repair, including relieving inflammation, promoting collagen deposition, and enhancing angiogenesis. Therefore, such self-healing supramolecular hydrogels with composite functional nanomaterials are expected to be used as new wound dressings in the field of healthcare.

Advance of Prussian Blue-Derived Nanohybrids in Energy Storage: Current Status and Perspective.

Great changes have occurred in the energy storage area in recent years as a result of rapid economic expansion. People have conducted substantial research on sustainable energy conversion and storage systems in order to mitigate the looming energy crisis. As a result, developing energy storage materials is critical. Materials with an open frame structure are known as Prussian blue analogs (PBAs). Anode materials for oxides, sulfides, selenides, phosphides, borides, and carbides have been extensively explored as anode materials in the field of energy conversion and storage in recent years. The advantages and disadvantages of oxides, sulfides, selenides, phosphides, borides, carbides, and other elements, as well as experimental methodologies and electrochemical properties, are discussed in this work. The findings reveal that employing oxides, sulfides, selenides, phosphides, borides, and other electrode materials to overcome the problems of low conductivity, excessive material loss, and low specific volume is ineffective. Therefore, this review intends to address the issues of diverse energy storage materials by combining multiple technologies to manufacture battery materials with low cost, large capacity, and extended service life.

Attenuated WNV-poly(A) exerts a broad-spectrum oncolytic effect by selective virus replication and CD8+ T cell-dependent immune response.

As an emerging tumor therapy, ideal oncolytic viruses preferentially replicate in malignant cells, reverse the immunosuppressive tumor microenvironment, and eventually can be eliminated by the patient. It is of great significance for cancer treatment to discover new excellent oncolytic viruses. Here, we found that WNV live attenuated vaccine WNV-poly(A) could be developed as a novel ideal oncolytic agent against several types of cancers. Mechanistically, due to its high sensitivity to type Ι interferon (IFN-Ι), WNV-poly(A) could specifically kill tumor cells rather than normal cells. At the same time, WNV-poly(A) could activate Dendritic cells (DCs) and trigger tumor antigen specific response mediated by CD8 + T cell, which contributed to inhibit the propagation of original and distal tumor cells. Like intratumoral injection, intravenous injection with WNV-poly(A) also markedly delays Huh7 hepatic carcinoma (HCC) transplanted tumor progression. Most importantly, in addition to an array of mouse xenograft tumor models, WNV-poly(A) also has a significant inhibitory effect on many different types of patient-derived tumor tissues and HCC patient-derived xenograft (PDX) tumor models. Our studies reveal that WNV-poly(A) is a potent and excellent oncolytic agent against many types of tumors and may have a role in metastatic and recurrent tumors.

Intranasal delivery of replicating mRNA encoding hACE2-targeting antibody against SARS-CoV-2 Omicron infection in the hamster.

The Omicron variant is sweeping the world, which displays striking immune escape potential through mutations at key antigenic sites on the spike protein, making broad-spectrum SARS-CoV-2 prevention or therapeutical strategies urgently needed. Previously, we have reported a hACE2-targeting neutralizing antibody 3E8, which could efficiently block both prototype SARS-CoV-2 and Delta variant infections in prophylactic mouse models, having the potential of broad-spectrum to prevent SARS-CoV-2. However, preparation of monoclonal neutralizing antibodies is severely limited by the time-consuming process and the relative high cost. Here, we utilized a modified VEEV replicon with two subgenomic (sg) promoters engineered to express the light and heavy chains of the 3E8 mAb. The feasibility and protective efficacy of replicating mRNA encoding 3E8 against Omicron infection in the hamster were demonstrated through the lung targeting delivery with the help of VEEV-VRP. Overall, we developed a safe and cost-effective platform of broad-spectrum to prevent SARS-CoV-2 infection.