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Journal of Ethnopharmacology Oct 2023Bu-Zhong-Yi-Qi-Tang is a famous traditional Chinese medicine formula that has been prevalent in China for over 700 years to treat spleen-qi deficiency related diseases,...
ETHNOPHARMACOLOGICAL RELEVANCE
Bu-Zhong-Yi-Qi-Tang is a famous traditional Chinese medicine formula that has been prevalent in China for over 700 years to treat spleen-qi deficiency related diseases, such as gastrointestinal and respiratory disorders. However, the bioactive components responsible for regulating spleen-qi deficiency remain unclear and have puzzled many researchers.
AIM OF THE STUDY
The current study focuses on efficacy evaluation of regulating spleen-qi deficiency and screening the bioactive components of Bu-Zhong-Yi-Qi-Tang.
MATERIALS AND METHODS
The effects of Bu-Zhong-Yi-Qi-Tang were evaluated through blood routine examination, immune organ index, and biochemical analysis. Metabolomics was utilized to analyze the potential endogenous biomarkers (endobiotics) in the plasma, and the prototypes (xenobiotics) of Bu-Zhong-Yi-Qi-Tang in the bio-samples were characterized using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Then, these endobiotics were used as "bait" to predict targets based on network pharmacology and to screen potential bioactive components from the absorbed prototypes in the plasma by constructing an "endobiotics-targets-xenobiotics" association network. Further, the anti-inflammatory activities of representative compounds (calycosin and nobiletin) were validated through poly(I:C)-induced pulmonary inflammation mice model.
RESULTS
Bu-Zhong-Yi-Qi-Tang exhibited immunomodulatory and anti-inflammatory activities in spleen-qi deficiency rat, as supported by the observation of increased levels of D-xylose and gastrin in serum, an increase in the thymus index and number of lymphocytes in blood, as well as a reduction in the level of IL-6 in bronchoalveolar lavage fluid. Furthermore, plasma metabolomic analysis revealed a total of 36 Bu-Zhong-Yi-Qi-Tang related endobiotics, which were mainly enriched in primary bile acids biosynthesis, the metabolism of linoleic acid, and the metabolism of phenylalanine pathways. Meanwhile, 95 xenobiotics were characterized in plasma, urine, small intestinal contents, and tissues of spleen-qi deficiency rat after Bu-Zhong-Yi-Qi-Tang treatment. Using an integrated association network, six potential bioactive components of Bu-Zhong-Yi-Qi-Tang were screened. Among them, calycosin was found to significantly reduce the levels of IL-6 and TNF-α in the bronchoalveolar lavage fluid, increase the number of lymphocytes, while nobiletin dramatically decreased the levels of CXCL10, TNF-α, GM-CSF, and IL-6.
CONCLUSION
Our study proposed an available strategy for screening bioactive components of BYZQT regulating spleen-qi deficiency based on "endobiotics-targets-xenobiotics" association network.
Topics: Mice; Rats; Animals; Spleen; Tumor Necrosis Factor-alpha; Interleukin-6; Xenobiotics; Drugs, Chinese Herbal; Anti-Inflammatory Agents
PubMed: 37178982
DOI: 10.1016/j.jep.2023.116605 -
Neurobiology of Stress Nov 2023Maternal infection during pregnancy and childhood social trauma have been associated with neurodevelopmental and affective disorders, such as schizophrenia, autism...
Maternal infection during pregnancy and childhood social trauma have been associated with neurodevelopmental and affective disorders, such as schizophrenia, autism spectrum disorders, bipolar disorder and depression. These disorders are characterized by changes in microglial cells, which play a notable role in synaptic pruning, and synaptic deficits. Here, we investigated the effect of prenatal infection and social adversity during adolescence - either alone or in combination - on behavior, microglia, and synaptic density. Male offspring of pregnant rats injected with poly I:C, mimicking prenatal infection, were exposed to repeated social defeat during adolescence. We found that maternal infection during pregnancy prevented the reduction in social behavior and increase in anxiety induced by social adversity during adolescence. Furthermore, maternal infection and social adversity, alone or in combination, induced hyperlocomotion in adulthood. Longitudinal in vivo imaging with [C]PBR28 positron emission tomography revealed that prenatal infection alone and social adversity during adolescence alone induced a transient increase in translocator protein TSPO density, an indicator of glial reactivity, whereas their combination induced a long-lasting increase that remained until adulthood. Furthermore, only the combination of prenatal infection and social adversity during adolescence induced an increase in microglial cell density in the frontal cortex. Prenatal infection increased proinflammatory cytokine IL-1β protein levels in hippocampus and social adversity reduced anti-inflammatory cytokine IL-10 protein levels in hippocampus during adulthood. This reduction in IL-10 was prevented if rats were previously exposed to prenatal infection. Adult offspring exposed to prenatal infection or adolescent social adversity had a higher synaptic density in the frontal cortex, but not hippocampus, as evaluated by synaptophysin density. Interestingly, such an increase in synaptic density was not observed in rats exposed to the combination of prenatal infection and social adversity, perhaps due to the long-lasting increase in microglial density, which may lead to an increase in microglial synaptic pruning. These findings suggest that changes in microglia activity and cytokine release induced by prenatal infection and social adversity during adolescence may be related to a reduced synaptic pruning, resulting in a higher synaptic density and behavioral changes in adulthood.
PubMed: 37920548
DOI: 10.1016/j.ynstr.2023.100580 -
Vaccines Jun 2024Sublingual vaccines offer the benefits of inducing mucosal immunity to protect against respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2...
Sublingual vaccines offer the benefits of inducing mucosal immunity to protect against respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and influenza, while also enabling needle-free self-administration. In a previous study, a sublingual SARS-CoV-2 vaccination was created by combining a recombinafigureCoV-2 spike protein receptor-binding domain antigen with a double strand RNA Poly(I:C) adjuvant. This vaccine was tested on nonhuman primates, Cynomolgus macaques. This study examined the immune and inflammatory responses elicited by the sublingual influenza vaccine containing hemagglutinin (HA) antigen and Poly(I:C) adjuvants, and assessed the safety of this vaccine in nonhuman primates. The Poly(I:C)-adjuvanted sublingual vaccine induced both mucosal and systemic immunities. Specifically, the sublingual vaccine produced HA-specific secretory IgA antibodies in saliva and nasal washings, and HA-specific IgA and IgG were detected in the blood. This vaccine appeared to be safe, as judged from the results of blood tests and plasma C-reactive protein levels. Notably, sublingual vaccination neither increased the production of inflammation-associated cytokines-IFN-alpha, IFN-gamma, and IL-17-in the blood, nor upregulated the gene expression of proinflammatory cytokines-IL12A, IL12B, IFNA1, IFNB1, CD69, and granzyme B-in white blood cells. Moreover, DNA microarray analyses revealed that sublingual vaccination evoked both enhancing and suppressing expression changes in genes associated with immune-related responses in cynomolgus monkeys. Therefore, the sublingual vaccine with the Poly(I:C) adjuvant is safe, and creates a balanced state of enhancing and suppressing the immune-related response.
PubMed: 38932372
DOI: 10.3390/vaccines12060643 -
Viruses Oct 2023Nipah virus (NiV; genus: Henipavirus; family: ) naturally infects Old World fruit bats (family ) without causing overt disease. Conversely, NiV infection in humans and...
Nipah virus (NiV; genus: Henipavirus; family: ) naturally infects Old World fruit bats (family ) without causing overt disease. Conversely, NiV infection in humans and other mammals can be lethal. Comparing bat antiviral responses with those of humans may illuminate the mechanisms that facilitate bats' tolerance. Tripartite motif proteins (TRIMs), a large family of E3-ubiquitin ligases, fine-tune innate antiviral immune responses, and two human TRIMs interact with Henipavirus proteins. We hypothesize that NiV infection induces the expression of an immunosuppressive TRIM in bat, but not human cells, to promote tolerance. Here, we show that TRIM40 is an interferon-stimulated gene (ISG) in pteropodid but not human cells. Knockdown of bat TRIM40 increases gene expression of IFNβ, ISGs, and pro-inflammatory cytokines following poly(I:C) transfection. In , but not human cells, NiV induces TRIM40 expression within 16 h after infection, and knockdown of TRIM40 correlates with reduced NiV titers as compared to control cells. Bats may have evolved to express TRIM40 in response to viral infections to control immunopathogenesis.
Topics: Animals; Humans; Chiroptera; Henipavirus Infections; Immunity, Innate; Interferons; Nipah Virus; Tripartite Motif Proteins; DEAD Box Protein 58
PubMed: 38005825
DOI: 10.3390/v15112147 -
Fish and Shellfish Immunology Reports Dec 2023Polyinosinic-polycytidylic acid (poly I:C) is a synthesized analogue of viral double-strand RNA and considered as a potential immunostimulant in aquaculture. MicroRNAs...
Polyinosinic-polycytidylic acid (poly I:C) is a synthesized analogue of viral double-strand RNA and considered as a potential immunostimulant in aquaculture. MicroRNAs (miRNAs) have been reported to play important roles in the development of the immune system and in regulation of host antiviral responses. In our earlier study, it was found that poly I:C pre-treatment could stimulate the resistance against cyprinid herpesvirus 2 (CyHV-2) infection and enhance the antiviral immune response in gibel carp. To understand the role of miRNAs in regulating the host response to poly I:C treatment, we investigated the expression profiles of miRNAs in the head kidney of poly I:C-treated gibel carp with small RNA sequencing technology. When compared with the untreated group, a total of 24 differentially expressed miRNAs were identified in the poly I:C-stimulated fish, among which, 7 and 17 miRNAs were upregulated and downregulated, respectively. Analysis of target genes of these differentially expressed miRNAs found that most targeted mRNAs were involved in catalytic activity, peptidase activity and endopeptidase activity, and were enriched in the metabolic, protein processing in endoplasmic reticulum and oxidative phosphorylation signaling pathways, suggesting that poly I:C could alter the expression of metabolism-related miRNAs in the kidney of gibel carp. Besides, it was noted that some immune-related miRNAs, including inflammation-related miRNAs (miR-192 and miR-731) and interferon-related miRNAs (miR-194a and miR-122), were downregulated after poly I:C treatment. In summary, it was found that poly I:C could regulate the cellular levels of specific miRNAs involved in metabolism and immune responses in the head kidney of gibel carp, which may increase the capacity of the immune cells to fight against pathogens infection.
PubMed: 36660301
DOI: 10.1016/j.fsirep.2023.100083 -
Placenta Oct 2023We investigated the proinflammatory functions of endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) in the development of...
OBJECTIVE
We investigated the proinflammatory functions of endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) in the development of gestational diabetes mellitus (GDM) and their relationship in regulating inflammation in GDM.
METHODS
This study was performed on placentas of normal pregnant women, women with GDM, and HTR8 cells. Transmission electron microscopy, immunohistochemistry, Western blot analysis, and RT-PCR were performed to analyze ERS and PPARα expression on both normal and GDM pregnancy placentas. ELISA was performed to analyze inflammatory biomarkers. To generate models of the GDM-like state, placentas of normal pregnancy were treated with LPS and polyinosinic-polycytidylic acid (poly [I:C]). TG, CHOP plasmid, and CHOP siRNA were assessed as to their regulation of HTR8 cells to discern the relationship between ERS and PPARα in regulating the inflammation associated with GDM.
RESULTS
ERS was elevated in GDM placentas, induced the secretion of IL-6 and TNF-α, and attenuated the expression of GLUT-4. PPARα was diminished in GDM placentas and inhibited the inflammatory responses via the NF-κB nuclear-transport process. 4-PBA reduced CHOP and augmented PPARα, and it decreased IL-6 and TNF-α in our GDM-like explant. However, with both 4-PBA and MK886 treatment, we noted no significant difference in CHOP expression. The level of PPARα was reduced, and that of NF-κB p65 in the nucleus was elevated with TG treatment in the HTR8/Svneo. Knockdown of CHOP increased PPARα and reduced NF-κB p65, while expression of PPARα declined, and that of NF-κB p65 rose with the application of CHOP when HTR8 cells were treated with TG.
CONCLUSIONS
ERS contributes to the pathophysiology of GDM in pregnancy via the CHOP-PPARα-NF-κB-signalling pathway by inducing aberrant activation of inflammation and insulin resistance.
PubMed: 37639950
DOI: 10.1016/j.placenta.2023.08.070 -
International Immunopharmacology Sep 2023Heatstroke is a life-threatening disease. Present study was aimed to investigate the mechanism in heat induced intestinal epithelial cell death.
BACKGROUND
Heatstroke is a life-threatening disease. Present study was aimed to investigate the mechanism in heat induced intestinal epithelial cell death.
METHOD
Heat stress in vitro model was established on IEC cells with 42℃ for 2 h. Caspase-8 inhibitor, Caspase-3 inhibitor, RIP3 inhibitor, TLR3 agonist, poly(I:C) and p53 knockdown were used to determine the signaling pathway. Heatstroke in vivo model was established on C57BL/6 mice, with a temperature of 35.5℃±0.5℃ and a relative humidity of 60% ± 5%. The intestine necroptosis and inflammatory cytokines were measured. Pifithrin α (3 mg/kg) and p53 knockout mice were used to evaluate the role of p53.
RESULTS
Heat stress-induced reduction of cell viability was remarkable reversed by RIP3 inhibitor. Heat stress induced upregulation of TLR3 and facilitate the formation of TRIF-RIP3 complex. The heat stress induced upregulation of RIP3 and p-RIP3 were normalized by the deletion of p53. Meanwhile, p53 knockout decreased TLR3 expression and blocked the formation of TLR3-TRIF complex. The deletion of p53 blocked the decreased cell viability and restored the activation of RIP3-MLKL signaling after heat stress, however, which were abolished by re-expression of p53 via Tp53 OE. Increased the expression of TLR3 in the p53-deficient cells could not affect the heat stress induced necrotic cell death, which suggests that heat stress induced necroptosis via TLR3-TRIF-RIP3 signaling pathway is dependent on p53.
CONCLUSION
Heat stress promoted p53 phosphorylation, then upregulated TLR3 and enhanced the interaction of TRIF-RIP3, which would activate the RIP3-MLKL signaling pathway to mediate necroptosis in intestinal epithelial cells.
Topics: Mice; Animals; Toll-Like Receptor 3; Necroptosis; Tumor Suppressor Protein p53; Mice, Inbred C57BL; Epithelial Cells; Intestines; Mice, Knockout; Heat Stroke; Heat-Shock Response; Adaptor Proteins, Vesicular Transport; Receptor-Interacting Protein Serine-Threonine Kinases; Apoptosis
PubMed: 37421775
DOI: 10.1016/j.intimp.2023.110574 -
Viruses Sep 2023Pacific oyster mortality syndrome (POMS), which is caused by (OsHV-1), causes economic losses in Pacific oyster () aquaculture in many countries. Reducing the mortality...
Pacific oyster mortality syndrome (POMS), which is caused by (OsHV-1), causes economic losses in Pacific oyster () aquaculture in many countries. Reducing the mortality in disease outbreaks requires changing the host, pathogen and environment interactions to favor the host. Survivors of natural exposure to OsHV-1 are able to survive subsequent outbreaks. This has been replicated under laboratory conditions, suggesting the existence of an immune response. The aim of the present study is to compare the effects of prior exposure to infectious OsHV-1, heat-inactivated OsHV-1 and the chemical anti-viral immune stimulant poly I:C on mortality following exposure to virulent OsHV-1. All treatments were administered by intramuscular injection. Oysters were maintained at 18 °C for 14 days; then, the temperature was increased to 22 °C and the oysters were challenged with virulent OsHV-1. Heat-inactivated OsHV-1, infectious OsHV-1 and poly I:C all induced significant protection against mortality, with the hazard of death being 0.41, 0.18 and 0.02, respectively, compared to the controls, which had no immune priming. The replication of OsHV-1 on first exposure was not required to induce a protective response. While the underlying mechanisms for protection remain to be elucidated, conditioning for resistance to POMS by prior exposure to inactivated or infectious OsHV-1 may have practical applications in oyster farming but requires further development to optimize the dose and delivery mechanism and evaluate the duration of protection.
PubMed: 37766349
DOI: 10.3390/v15091943 -
Behavioural Brain Research Feb 2024Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with uncertain etiology and pathophysiology. Several studies revealed that the commonly used...
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with uncertain etiology and pathophysiology. Several studies revealed that the commonly used animal models like Valproic Acid (VPA) and Propionic Acid (PPA) do not precisely represent the disease as the human patient does. The current study was conducted on different chemically (VPA, PPA, Poly I:C, Dioxin (2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)) & Chlorpyrifos (CPF)) induced ASD-like animal models and validated the best suitable experimental animal model, which would closely resemble with clinical features of the ASD. This validated model might help to explore the pathophysiology of ASD. This study included rat pups prenatally exposed to VPA, PPA, Poly I:C, Dioxin & CPF within GD9 to GD15 doses. The model groups were validated through developmental and behavioral parameters, Gene Expressions, Oxidative Stress, and Pro-inflammatory and Anti-inflammatory cytokines levels. Developmental and neurobehavioral parameters showed significant changes in model groups compared to the control. In oxidative stress parameters and neuro-inflammatory cytokines levels, model groups exhibited high oxidative stress and neuro-inflammation compared to control groups. Gene expression profile of ASD-related genes showed significant downregulation in model groups compared to the control group. Moreover, the Poly I:C group showed more significant results than other model groups. The comparison of available ASD-like experimental animal models showed that the Poly I:C induced model represented the exact pathophysiology of ASD as the human patient does. Poly I:C was reported in the maternal immune system activation via the inflammatory cytokines pathway, altering embryonic development and causing ASD in neonates.
Topics: Humans; Pregnancy; Female; Rats; Animals; Rats, Wistar; Autism Spectrum Disorder; Dioxins; Valproic Acid; Cytokines; Chlorpyrifos; Poly I; Disease Models, Animal; Prenatal Exposure Delayed Effects; Behavior, Animal
PubMed: 37923221
DOI: 10.1016/j.bbr.2023.114728 -
International Immunopharmacology May 2024Increased expression of CXCL10 and its receptor CXCR3 represents an inflammatory response in cells and tissues. Macrophage polarization and autophagy are major functions...
Increased expression of CXCL10 and its receptor CXCR3 represents an inflammatory response in cells and tissues. Macrophage polarization and autophagy are major functions in inflammatory macrophages; however, the cellular functions of the CXCL10-CXCR3 axis in macrophages are not well understood. Here, we examined the role of CXCL10-CXCR3-axis-regulated autophagy in macrophage polarization. First, in non-inflammatory macrophages, whereas CXCL10 promotes M2 polarization and inhibits M1 polarization, CXCR3 antagonist AMG487 induces the opposite macrophage polarization. Next, CXCL10 promotes the expression of autophagy proteins (Atg5-Atg12 complex, p62, LC3-II, and LAMP1) and AMG487 inhibits their expression. Knockdown of LAMP1 by short interfering RNA switches the CXCL10-induced polarization from M2 to M1 in non-inflammatory macrophages. Furthermore, in inflammatory macrophages stimulated by poly(I:C), CXCL10 induces M1 polarization and AMG487 induces M2 polarization in association with a decrease in LAMP1. Finally, AMG487 alleviates lung injury after poly(I:C) treatment in mice. In conclusion, CXCL10-CXCR3 axis differentially directs macrophage polarization in inflammatory and non-inflammatory states, and autophagy protein LAMP1 acts as the switch controlling the direction of macrophage polarization by CXCL10-CXCR3.
Topics: Animals; Receptors, CXCR3; Chemokine CXCL10; Macrophages; Mice; Mice, Inbred C57BL; Autophagy; Inflammation; Poly I-C; Lysosomal Membrane Proteins; Male; Signal Transduction; Humans; Macrophage Activation; Acetamides; Pyrimidinones
PubMed: 38555817
DOI: 10.1016/j.intimp.2024.111929