Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway.

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.

A mutual regulatory loop between transcription factor Yin Yang 1 and hepatitis B virus replication influences chronic hepatitis B.

Hepatitis B virus (HBV) infections pose a major threat to human health. HBV can upregulate the expression of the transcription factor Yin Yang 1 (YY1) in in vitro cytological experiments, suggesting an association between YY1 and HBV infection. However, data on YY1 expression in chronic hepatitis B (CHB) patients are lacking. In this study, we aimed to assess the correlation between YY1 expression and HBV infection. We detected serum YY1 levels in 420 patients with chronic HBV infection, 30 patients with chronic hepatitis C virus infection, and 32 healthy controls using an enzyme-linked immunosorbent assay. The correlation between YY1 levels and clinical parameters was analyzed. Meanwhile, the changes of YY1 before and after interferon or entecavir treatment were analyzed. YY1 levels in the liver tissues were detected using immunofluorescence staining. The expression of YY1 in HBV-expressing cells was detected through western blotting. Meanwhile, we explored the effects of YY1 on HBV replication and gene expression. We found that YY1 was highly expressed in the serum and liver tissues of CHB patients. Serum YY1 levels positively correlated with HBV DNA and hepatitis B surface antigen (HBsAg). Additionally, HBV DNA levels increased but HBsAg levels decreased after HBV-expressing cells overexpress YY1. In conclusion, our study demonstrates that YY1 plays an important role in HBV replication and gene expression, providing a potential target for the treatment of CHB.

Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway.

OBJECTIVE: This work explores the impact of electroacupuncture (EA) on acute postoperative pain (APP) and the role of stimulator of interferon genes/type-1 interferon (STING/IFN-1) signaling pathway modulation in the analgesic effect of EA in APP rats. METHODS: The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints. Mechanical, thermal and cold sensitivity tests were performed to measure the pain threshold, and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP. Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation. A STING inhibitor (C-176) was administered intrathecally to verify its role in EA. RESULTS: APP rats displayed mechanical and thermal hypersensitivities compared to the control group (P < 0.05). APP significantly reduced the amplitude of θ, α and γ oscillations compared to their baseline values (P < 0.05). Interestingly, expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP (P < 0.05). Further, APP increased pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and inducible nitric oxide synthase, and downregulated anti-inflammatory factors, including interleukin-10 and arginase-1 (P < 0.05). EA effectively attenuated APP-induced painful hypersensitivities (P < 0.05) and restored the θ, α and γ power in APP rats (P < 0.05). Meanwhile, EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response (P < 0.05). Furthermore, STING/IFN-1 was predominantly expressed in isolectin-B4- or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn. Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP (P < 0.05). CONCLUSION: EA can generate robust analgesic and anti-inflammatory effects on APP, and these effects may be linked to activating the STING/IFN-1 pathway, suggesting that STING/IFN-1 may be a target for relieving APP. Please cite this article as: Ding YY, Xu F, Wang YF, Han LL, Huang SQ, Zhao S, Ma LL, Zhang TH, Zhao WJ, Chen XD. Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway. J Integr Med. 2023; 21(5): 496-508.

Novel human STING activation by hydrated-prenylated xanthones from Garcinia cowa.

OBJECTIVES: We investigate the anticancer activity and human stimulator of interferon genes pathway activation by a new hydrated-prenylated tetraoxygenated xanthone, garcicowanone I (1) and two known xanthones (2 and 3) that were isolated from the root bark of Garcinia cowa Roxb. ex Choisy. METHODS: The anticancer activity of each compound was evaluated by sulforhodamine B assay in immortalized cancer cell lines. Stimulator of interferon genes pathway activation was assessed by western blot analysis using human THP-1-derived macrophages. The production of pro-inflammatory cytokines from these macrophages was also evaluated via enzyme-linked immunosorbent assay. KEY FINDINGS: Both compounds 1 and 3 displayed moderate inhibitory effects on the cancer cells, including a cisplatin-resistant cell line, with IC50 values in the range of 10-20 µM. All three xanthones activated the stimulator of interferon genes, as evidenced by phosphorylation of tank-binding kinase 1, the stimulator of interferon genes protein and interferon regulatory factor 3. Furthermore, treatment of these macrophages with compounds 1-3 led to the production of pro-inflammatory cytokines, including interleukin 6, tumour necrosis factor α and interleukin 1ß. CONCLUSIONS: In conclusion, the isolated xanthones, including the novel garcicowanone I, displayed promising anticancer and immunomodulatory activity that warrants further research.

Identification of potent target and its mechanism of action of Tripterygium wilfordii Hook F in the treatment of lupus nephritis.

AIM: The Chinese anti-rheumatic herbal remedy Tripterygium wilfordii Hook F (TWHF) has been widely shown to be effective in treating lupus nephritis (LN), but the therapeutic targets and mechanisms of action are still unclear. In this study, we aimed to combine mRNA expression profile analysis and network pharmacology analysis to screen the pathogenic genes and pathways involved in LN and to explore the potential targets of TWHF in the treatment of LN. METHODS: The mRNA expression profiles of LN patients were used to screen differentially expressed genes (DEGs) and to predict associated pathogenic pathways and networks via the Ingenuity Pathway Analysis database. Through molecular docking, we predicted the mechanism by which TWHF interacts with candidate targets. RESULTS: A total of 351 DEGs were screened from the glomeruli of LN patients and were mainly concentrated in the role of pattern recognition receptors in the recognition of bacteria and viruses and interferon signaling pathways. A total of 130 DEGs were screened from the tubulointerstitium of LN patients, which were concentrated in the interferon signaling pathway. TWHF might be effective in treating LN by hydrogen bonding to regulate the functions of 24 DEGs (including HMOX1, ALB, and CASP1), which are mainly concentrated in the B-cell signaling pathway. CONCLUSION: The mRNA expression profile of renal tissue from LN patients revealed a large number of DEGs. TWHF has been shown to interact with the DEGs (including HMOX1, ALB and CASP1) through hydrogen bonding to treat LN.

Modulatory properties of curcumin in cancer: A narrative review on the role of interferons.

The immune network is an effective network of cell types and chemical compounds established to maintain the body's homeostasis from foreign threats and to prevent the risk of a wide range of diseases; hence, its proper functioning and balance are essential. A dysfunctional immune system can contribute to various disorders, including cancer. Therefore, there has been considerable interest in molecules that can modulate the immune network. Curcumin, the active ingredient of turmeric, is one of these herbal remedies with many beneficial effects, including modulation of immunity. Curcumin is beneficial in managing various chronic inflammatory conditions, improving brain function, lowering cardiovascular disease risk, prevention and management of dementia, and prevention of aging. Several clinical studies have supported this evidence, suggesting curcumin to have an immunomodulatory and anti-inflammatory function; nevertheless, its mechanism of action is still not clear. In the current review, we aim to explore the modulatory function of curcumin through interferons in cancers.

Melatonin Suppresses Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Signaling and Delays the Development of Hearing Loss in the C57BL/6J Presbycusis Mouse Model.

Melatonin supplementation has been shown to delay age-related hearing loss (ARHL) progression. Previously, melatonin was found to inhibit neuronal mitochondrial DNA (mtDNA) release, as well as inhibit cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby delaying the onset of central nervous system diseases. Therefore, we hypothesized that melatonin may delay the progression of hearing loss in the C57BL/6J presbycusis mouse model by inhibiting cGAS-STING signaling in the auditory pathway. Oral melatonin at 10 mg/kg/d was administered to 3-month-old C57BL/6J mice until 12 months of age. The auditory brainstem response (ABR) threshold was used to assess their hearing ability. By real-time polymerase chain reaction and Western blot analysis, the levels of cytosolic mtDNA, cGAS/STING, and cytokines were examined in the mouse cochlea, inferior colliculus, and auditory cortex. We found that the 12-month-old control mice exhibited significant hearing loss, increased cytosolic mtDNA, increased expression of inflammatory factors TNF-α, IL-6, IFN-ß, Cxcl10, and Ifit3, up-regulated cGAS and STING expression, and enhanced interferon regulatory factor 3 (IRF3) phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. Melatonin treatment significantly improved hearing, decreased cytosolic mtDNA, suppressed the expression of inflammatory cytokines TNF-α, IL-6, IFN-ß, Ifit3, and Cxcl10, down-regulated cGAS and STING expression, and attenuated IRF3 phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. This study suggested that melatonin had a protective effect on auditory function in the C57BL/6J presbycusis mouse model, which may be mediated through reducing mtDNA release, inhibiting the cGAS-STING signaling pathway in the auditory pathway.

Multifaceted Effects and Mechanisms of N-Acetylcysteine on Intestinal Injury in a Porcine Epidemic Diarrhea Virus-Infected Porcine Model.

SCOPE: This study investigates the potential effects of N-acetylcysteine (NAC) on intestinal injury in a porcine epidemic diarrhea virus (PEDV)-infected porcine model. METHODS AND RESULTS: Thirty-two piglets are randomly assigned to one of four groups: the control, PEDV, NAC, and NAC+PEDV. Piglets in the NAC+PEDV group are orally administrated with NAC (100 mg (kg·BW)-1  day-1 ) for 4 consecutive days after 2 days of PEDV infection. The results show that NAC administration decreases the diarrhea rate and improves intestinal morphology. The concentration of diamine oxidase and intestinal fatty-acid binding protein, as well as IL-1ß, IL-8, and TNF-α in the plasma, is decreased by NAC. Intriguingly, NAC administration significantly increases the viral load in the jejunum and ileum and down-regulates the expression of interferon-related genes. Microarray and proteomic analyses show that the differentially expressed genes/proteins between NAC+PEDV and PEDV groups are highly enriched in substance transport. Furthermore, aquaporin 8/10 expression is significantly increased by NAC upon PEDV infection. CONCLUSION: NAC administration alleviates PEDV-induced intestinal injury by inhibiting inflammatory responses and improving substance transport, but promotes viral replication by inhibiting interferon signaling. These results suggest NAC exhibits multifaceted effects upon PEDV infection, and thus caution is required when using NAC as a dietary supplement to prevent viral infection.

Alzheimer's disease large-scale gene expression portrait identifies exercise as the top theoretical treatment.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

Grape Pomace Polyphenols as a Source of Compounds for Management of Oxidative Stress and Inflammation-A Possible Alternative for Non-Steroidal Anti-Inflammatory Drugs?

Flavonoids, stilbenes, lignans, and phenolic acids, classes of polyphenols found in grape pomace (GP), were investigated as an important alternative source for active substances that could be used in the management of oxidative stress and inflammation. The benefic antioxidant and anti-inflammatory actions of GP are presented in the literature, but they are derived from a large variety of experimental in vitro and in vivo settings. In these in vitro works, the decrease in reactive oxygen species, malondialdehyde, and thiobarbituric acid reactive substances levels and the increase in glutathione levels show the antioxidant effects. The inhibition of nuclear factor kappa B and prostaglandin E2 inflammatory pathways and the decrease of some inflammatory markers such as interleukin-8 (IL-8) demonstrate the anti-inflammatory actions of GP polyphenols. The in vivo studies further confirmed the antioxidant (increase in catalase, superoxide dismutase and glutathione peroxidase levels and a stimulation of endothelial nitric oxide synthase -eNOS gene expression) and anti-inflammatory (inhibition of IL-1𝛼, IL-1ß, IL-6, interferon-𝛾, TNF-α and C-reactive protein release) activities. Grape pomace as a whole extract, but also different individual polyphenols that are contained in GP can modulate the endogenous pathway responsible in reducing oxidative stress and chronic inflammation. The present review analyzed the effects of GP in oxidative stress and inflammation, suggesting that it could become a valuable therapeutic candidate capable to reduce the aforementioned pathological processes. Grape pomace extract could become an adjuvant treatment in the attempt to reduce the side effects of the classical anti-inflammatory medication like non-steroidal anti-inflammatory drugs (NSAIDs).

Effects of Dietary Supplementation with Carrot-Derived Rhamnogalacturonan-I (cRG-I) on Accelerated Protective Immune Responses and Quality of Life in Healthy Volunteers Challenged with Rhinovirus in a Randomized Trial.

An adequate and balanced supply of nutrients is essential for maintaining health, and an optimal immune response is fast, contained and properly controlled, curbing infections quickly while minimizing damage. Several micronutrients contribute to normal immune function and certain dietary fibers, for example pectic polysaccharides, can play an important role in educating and regulating immune cell responses. The aim of this paper is to elaborate on our initial findings that dietary supplementation with carrot-derived rhamnogalacturonan-I (cRG-I) accelerates and augments local innate immune and anti-viral interferon response to a rhinovirus-16 (RV16) infection and reduces the severity and duration of symptoms in humans. Dietary intake of cRG-I also enhanced immune responses to this respiratory viral infection as measured by ex vivo stimulation of whole blood with the Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid and NK cell function. Consumption of cRG-I also reduced the negative effects of this common cold infection on quality of life as assessed by individual symptom scores. RG-I from carrot is a safe, sustainable, and economically viable solution that could easily be integrated into food products and dietary supplements aiming to support immune fitness and wellbeing.

Actin cytoskeleton remodeling primes RIG-I-like receptor activation.

The current dogma of RNA-mediated innate immunity is that sensing of immunostimulatory RNA ligands is sufficient for the activation of intracellular sensors and induction of interferon (IFN) responses. Here, we report that actin cytoskeleton disturbance primes RIG-I-like receptor (RLR) activation. Actin cytoskeleton rearrangement induced by virus infection or commonly used reagents to intracellularly deliver RNA triggers the relocalization of PPP1R12C, a regulatory subunit of the protein phosphatase-1 (PP1), from filamentous actin to cytoplasmic RLRs. This allows dephosphorylation-mediated RLR priming and, together with the RNA agonist, induces effective RLR downstream signaling. Genetic ablation of PPP1R12C impairs antiviral responses and enhances susceptibility to infection with several RNA viruses including SARS-CoV-2, influenza virus, picornavirus, and vesicular stomatitis virus. Our work identifies actin cytoskeleton disturbance as a priming signal for RLR-mediated innate immunity, which may open avenues for antiviral or adjuvant design.

An Unexpected Encounter: Respiratory Syncytial Virus Nonstructural Protein 1 Interacts with Mediator Subunit MED25.

Human respiratory syncytial virus (RSV) is the leading cause of severe acute lower respiratory tract infections in infants worldwide. Nonstructural protein NS1 of RSV modulates the host innate immune response by acting as an antagonist of type I and type III interferon (IFN) production and signaling in multiple ways. Likely, NS1 performs this function by interacting with different host proteins. In order to obtain a comprehensive overview of the NS1 interaction partners, we performed three complementary protein-protein interaction screens, i.e., BioID, MAPPIT, and KISS. To closely mimic a natural infection, the BioID proximity screen was performed using a recombinant RSV in which the NS1 protein is fused to a biotin ligase. Remarkably, MED25, a subunit of the Mediator complex, was identified in all three performed screening methods as a potential NS1-interacting protein. We confirmed the interaction between MED25 and RSV NS1 by coimmunoprecipitation, not only upon overexpression of NS1 but also with endogenous NS1 during RSV infection. We also demonstrate that the replication of RSV can be enhanced in MED25 knockout A549 cells, suggesting a potential antiviral role of MED25 during RSV infection. Mediator subunits function as transcriptional coactivators and are involved in transcriptional regulation of their target genes. Therefore, the interaction between RSV NS1 and cellular MED25 might be beneficial for RSV during infection by affecting host transcription and the host immune response to infection. IMPORTANCE Innate immune responses, including the production of type I and III interferons, play a crucial role in the first line of defense against RSV infection. However, only a poor induction of type I IFNs is observed during RSV infection, suggesting that RSV has evolved mechanisms to prevent type I IFN expression by the infected host cell. A unique RSV protein, NS1, is largely responsible for this effect, probably through interaction with multiple host proteins. A better understanding of the interactions that occur between RSV NS1 and host proteins may help to identify targets for an effective antiviral therapy. We addressed this question by performing three complementary protein-protein interaction screens and identified MED25 as an RSV NS1-interacting protein. We propose a role in innate anti-RSV defense for this Mediator complex subunit.

The involvement of an interferon-induced protein 44-like (CgIFI44L) in the antiviral immune response of Crassostrea gigas.

Interferon-stimulated genes (ISGs) encoding proteins are the essential executors of interferon (IFN) mediated antiviral defense. In the present study, an ISG member, interferon-induced protein 44-like (IFI44L) gene (designed as CgIFI44L-1) was identified from the Pacific oyster Crassostrea gigas. The ORF of CgIFI44L-1 cDNA was of 1437 bp encoding a polypeptide of 479 amino acids with a TLDc domain and an MMR_HSR1 domain. The mRNA transcripts of CgIFI44L-1 were detected in all the tested tissues with highest level in haemocytes, which was 15.78-fold of that in gonad (p < 0.001). Among the haemocytes, the CgIFI44L-1 protein was detected to be highly expressed in granulocytes with dominant distribution in cytoplasm. The mRNA expression level of CgIFI44L-1 in haemocytes was significantly induced by poly (I:C) stimulation, and the expression level peaked at 24 h, which was 24.24-fold (p < 0.0001) of that in control group. After the treatment with the recombinant protein of an oyster IFN-like protein (rCgIFNLP), the mRNA expression level of CgIFI44L-1 was significantly enhanced at 6 h, 12 h and 24 h, which was 2.67-fold (p < 0.001), 5.44-fold (p < 0.001) and 5.16-fold (p < 0.001) of that in control group, respectively. When the expressions of CgSTAT and CgIFNLP were knocked down by RNA interference (RNAi), the mRNA transcripts of CgIFI44L-1 were significantly down-regulated after poly (I:C) stimulation, which was 0.09-fold (p < 0.001) and 0.06-fold (p < 0.001) of those in EGFP group, respectively. These results suggested that CgIFI44L-1 was a conserved ISG in oyster, which was regulated by CgIFNLP and CgSTAT, and involved in the oyster antiviral immune response.

Rational Design of T-Cell- and B-Cell-Based Therapeutic Cancer Vaccines.

Cancer vaccines provide an efficient strategy to enhance tumor-specific immune responses by redeploying immune systems. Despite the approval of the first cancer vaccine (Sipuleucel-T) by the U.S. Food and Drug Administration in 2010, most therapeutic cancer vaccines fail in clinical trials. Basically, tumor-specific immune responses rely on not only T-cell but also B-cell immunity, which indicates that cancer vaccines should leverage both arms of the adaptive immune system. For example, CD8+ T cells activated by antigen-presenting cells (APCs) recognize and directly kill tumor cells via peptide-bound major histocompatibility complex (pMHC). B cells recognize antigen with no need of pMHC and require CD4+ T cells for sufficient activation and antibody generation, enabling antibody-mediated nondirect killing on tumor cells. Considering the different mechanisms of T-cell and B-cell activation, the rational design of therapeutic cancer vaccines should consider several factors, including antigen selection and recognition, immune activation, vaccine delivery, and repeatable vaccination, which can be advanced by chemical strategies.In this Account, we summarize our recent contributions to the development of effective T-cell- and B-cell-based therapeutic cancer vaccines. For T-cell-based vaccines, we focus on adjuvants as the key component for controllable APC activation and T-cell priming. Not only synthetic molecular agonists of pattern recognition receptors (PRRs) but also adjuvant nanomaterials were explored to satisfy diversiform vaccine designs. For example, a type of natural cyclic dinucleotide (CDN) that was chemically modified with fluorination and ipsilateral phosphorothioation to activate the stimulator of interferon gene (STING) was found to mediate antitumor responses. It retains structural similarity to the parent CDN scaffold but possesses increased stability, cellular uptake, and immune activation for antitumor treatment. It also facilitates facile conjugation with other agonists, which not only enhances APC-targeting delivery but also balances cellular and humoral antitumor responses. We also explored the intrinsic properties of nanomaterials that allow them to serve as adjuvants. A black phosphorus nanosheet-based nanovaccine was constructed and found to strongly potentiate antigen-specific T-cell antitumor immune responses through multiple immune-potentiating properties, leading to a highly integrated nanomaterial-based adjuvant design. For B-cell-based vaccines, multicomponent and multivalent strategies were applied to improve the immunogenicity. A multicomponent linear vaccine conjugate coordinates helper T (Th) cells and APCs to proliferate and differentiates B cells for enhanced antitumor immunoglobulin G antibody responses. To further improve antigen recognition, clustered designs on a multivalent epitope were applied by generating various structures, including branched lysine-based peptides, natural multivalent scaffold molecules, and self-assembled nanofibers. We also engineered nano- and microvaccine systems to optimize systemic and localized vaccination. A multilayer-assembled nanovaccine successfully integrated antigens and multiple agonists to modulate APC activation. A DNA hydrogel contributed to the control of APC's immune behaviors, including cell recruitment, activation, and migration, and induced robust antitumor responses as an all-in-one designable platform. In this Account, by summarizing strategies for both T-cell- and B-cell-based vaccine design, we not only compare the differences but also address the intrinsic uniformity between such vaccine designs and further discuss the potential of a combined T-cell- and B-cell-based vaccine, which highlights the applicability and feasibility of chemical strategies.

Efficacy of Interferon-Based Therapy for COVID-19: A Systematic Review and Meta-Analysis.

Background: The aim of this study was to determine the efficacy of interferon (IFN)-based therapy for coronavirus disease 2019 (COVID-19) based on relevant qualified studies. We searched for pertinent studies using keywords via PubMed, Cochrane and Embase databases. Studies from other pertinent sources and that were published before September 2021 were also reviewed. Methods: For each study, we assessed and synthesized the outcomes by relative risk (RR) or weighted mean difference (WMD) combined with a 95% confidence interval (CI). A total of 8 studies involving 2442 patients with COVID-19 were evaluated in this meta-analysis. Results: The IFN group had a significant decrease in ICU admissions (RR: 0.705; 95% CI, 0.515-0.964) and death (RR: 0.416; 95% CI, 0.217-0.797), and increased duration of ICU stay (WMD: 0.996; 95% CI, 0.834-1.158) compared with the control group in the randomized clinical trial (RCT) subgroup analysis. In non-RCT subgroup analysis, the IFN group showed a significant increase in discharge rate (RR: 1.052; 95% CI, 1.004-1.101) compared with the control group. Conclusion: IFN therapy appears to have better efficacy than non-IFN therapy as sedatives in patients with COVID-19 in terms of decreasing ICU admissions and death and increasing discharge. However, more high-quality RCTs are needed to confirm these findings.

Long-term survival with sorafenib-based multidisciplinary treatment for Vp4 hepatocellular carcinoma: a case report.

The prognosis of highly advanced unresectable hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT) is poor. There are currently no reports of long-term survival for up to 5 years in patients with advanced HCC who were treated with sorafenib. We describe a patient with Vp4 HCC who was treated with a sorafenib-based multidisciplinary treatment and experienced long-term survival, which may be the longest survival to date. A man in his late 60 s presented with general fatigue. Eight years previously, he received interferon monotherapy for chronic hepatitis C for 48 weeks and achieved a sustained virological response. He was diagnosed with a PVTT (Vp4) with diffuse-type HCC in the S6 lobe of the liver. He received hepatic arterial infusion of chemotherapy using 5-fluorouracil and cisplatin. Because of the occurrence of adverse effects, he was placed on sorafenib treatment. The treatment was effective and the HCC reduced. However, after 3 years of treatment, a 2-cm HCC was observed in the S5 lobe, and the patient underwent laparoscopic partial hepatectomy. After the operation, he continued to receive sorafenib, with no obvious recurrence, and survived for over 108 months after the first treatment. There are currently no reported cases of long-term progression-free survival by sorafenib for five years in patients of Vp4 HCC. In conclusion, we report a case of longest survival of a patient with Vp4 HCC treated with sorafenib-based multidisciplinary treatment.

Shenkang injection protects against renal fibrosis by reducing perforin expression through the STING/TBK1/IRF3 signaling pathways in natural killer cells.

BACKGROUND: Immune activation, chronic inflammation, and renal interstitial fibrosis (RIF) are associated with chronic kidney disease (CKD). The herbal formula, Shenkang injection (SKI), has been reported to attenuate RIF. However, the mechanisms by which SKI alleviates renal fibrosis, especially the role of natural killer (NK) cells, are unknown and require exploration. PURPOSE: This study aimed to determine the mechanisms by which SKI alleviates RIF. METHODS: Differential gene expression between CKD mice and control groups was explored using bioinformatics analysis. To reveal how SKI reduces RIF in CKD, a CKD mouse model was established using folic acid for in vivo studies, and human kidney-2 cells were used for in vitro experiments. The effects of various SKI doses were then determined. Immunohistochemical staining, Enzyme-linked immunosorbent assay, western blotting, and quantitative real-time PCR were used for pathological and molecular expression detection. RESULTS: We first investigated the potential immune dysfunction in CKD using bioinformatics analysis. Some differentially expressed genes were enriched in immune-related functions. The expressions of perforin and interferon (IFN)-γ, which are mainly released by NK cells, were significantly higher in patients with CKD (p< 0.05). In vivo experiments showed that SKI alleviated renal fibrosis in a folic acid-induced renal fibrosis model. Serum creatinine and blood urea nitrogen levels were reduced in the high-dose SKI-treated group. Additionally, the mRNA and protein expression levels of type IV collagen and alpha-spinal muscular atrophy were reduced. Biochemical detection showed that SKI could also downregulate the activity of NK cells (by decreasing the expressions of perforin and IFN-γ). Increased levels of stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1)/IFN regulatory factor 3 (IRF3), phosphorylation of TBK1, and IRF3 in FA-induced RIF mice were alleviated by SKI treatment, which was consistent with the results of in vitro experiments. CONCLUSION: These results demonstrated that SKI could decrease the activation of NK cells via the STING/TBK1/IRF3 signaling pathway, thereby alleviating RIF and protecting renal function in CKD. This may provide valuable evidence supporting the clinical use of SKI in the treatment of patients with CKD.

[Research progress on activities and mechanisms of anti-hepatitis B virus drugs].

Hepatitis B virus(HBV) is the pathogen causing hepatitis B, which is characterized by strong infectivity, high incidence, and widespread prevalence and has seriously threatened human health and affected their quality of life. Anti-HBV drugs in western medicine mainly include nucleosides(nucleic acids) and interferons, among which nucleosides(nucleic acids) are used more often. Due to the easy development of drug resistance, their therapeutic effects are not remarkable. Interferons can easily cause serious adverse reactions such as liver injury. Anti-HBV drugs in traditional Chinese medicine mainly include single Chinese herbs(Artemisiae Scopariae Herba, Artemisiae Annuae Herba, Salviae Miltiorrhizae Radix et Rhizoma, etc.) and Chinese herbal compounds(Yinchenhao Decoction, Xiaochaihu Decoction, Tiaogan Huaxian Pills, etc.), whose chemical compositions and action targets have not been fully identified. The combined medication is better than single medication, in that the former can improve drug resistance, make up each other's deficiencies, reduce adverse reactions, and prolong the action time. This study reviewed the anti-HBV activities and mechanisms of western drugs, Chinese herbs, and combined medications, in order to provide reference for the development and research of new anti-HBV drugs.

Form of dietary selenium affects mRNA encoding interferon-stimulated and progesterone-induced genes in the bovine endometrium and conceptus length at maternal recognition of pregnancy.

Widespread regions of the southeast United States have soils, and hence forages, deficient in selenium (Se), necessitating Se supplementation to grazing cattle for optimal immune function, growth, and fertility. We have reported that supplementation with an isomolar 1:1 mix (MIX) of inorganic (ISe) and organic (OSe) forms of Se increases early luteal phase (LP) concentrations of progesterone (P4) above that in cows on ISe or OSe alone. Increased early LP P4 advances embryonic development. Our objective was to determine the effects of the form of Se on the development of the bovine conceptus and the endometrium using targeted real-time PCR (qPCR) on day 17 of gestation, the time of maternal recognition of pregnancy (MRP). Angus-cross yearling heifers underwent 45-d Se-depletion then repletion periods, then at least 90 d of supplementation (TRT) with 35 ppm Se per day as either ISe (n = 10) or MIX (n = 10). Heifers were inseminated to a single sire after detected estrus (day 0). On day 17 of gestation, caruncular (CAR) and intercaruncular (ICAR) endometrial samples and the developing conceptus were recovered from pregnant heifers (ISe, n = 6 and MIX, n = 6). qPCR was performed to determine the relative abundance of targeted transcripts in CAR and ICAR samples, with the expression data subjected to one-way ANOVA to determine TRT effects. The effect of TRT on conceptus development was analyzed using a one-tailed Student's t-test. When compared with ISe-treated heifers, MIX heifers had decreased (P < 0.05) abundance of several P4-induced and interferon-stimulated mRNA transcripts, including IFIT3, ISG15, MX1, OAS2, RSAD2, DGAT2, FGF2 in CAR and DKK1 in ICAR samples and tended (P ≤ 0.10) to have decreased mRNA abundance of IRF1, IRF2, FOXL2, and PGR in CAR samples, and HOXA10 and PAQR7 in ICAR samples. In contrast, MIX-supplemented heifers had increased (P < 0.05) mRNA abundance of MSTN in ICAR samples and an increase in conceptus length (ISe: 17.45 ± 3.08 cm vs. MIX: 25.96 ± 3.95 cm; P = 0.05). Notably, myostatin increases glucose secretion into histotroph and contributes to advanced conceptus development. This advancement in conceptus development occurred in the presence of similar concentrations of serum P4 (P = 0.88) and whole blood Se (P = 0.07) at MRP.

In regions with soils deficient in selenium (Se), it is recommended that this trace mineral is supplemented to the diet of forage-grazing cattle. We have previously reported that the form of Se supplemented to cattle affects the function of multiple tissues, including the testis, liver, ovary, and pituitary. The objective of this study was to determine how the form of Se supplemented to heifers to achieve a Se-adequate status affects endometrial function and development of the conceptus at maternal recognition of pregnancy (MRP). Heifers were supplemented with the industry standard, an inorganic form of Se (ISe), or a 1:1 mix of organic and inorganic forms (MIX), with the reproductive tract recovered on day 17 of pregnancy. Real-time PCR was performed to determine the relative abundance of targeted mRNA transcripts in caruncular (CAR) and intercaruncular (ICAR) endometrial samples. The form of supplemental Se affected the abundance of multiple progesterone-induced and interferon-stimulated mRNA transcripts in CAR and ICAR samples, as well as the length of the conceptus that was recovered at MRP (day 17). Overall, our results indicate differences in endometrial function and increased development of the conceptus in cattle provided with MIX vs. ISe, suggesting that the MIX form of supplemental Se may increase fertility in cattle grazing soils deficient in this trace mineral.