Plant-derived exosome-like nanoparticles (ELNs) have been proposed as a novel therapeutic tool for preventing human diseases. However, the number of well-verified plant ELNs remains limited. In this ...study, the microRNAs in ELNs derived from fresh Rehmanniae Radix, a well-known traditional Chinese herb for treating inflammatory and metabolic diseases, were determined by using microRNA sequencing to investigate the active components in the ELNs and the protection against lipopolysaccharide (LPS)-induced acute lung inflammation in vivo and in vitro. The results showed that rgl-miR-7972 (miR-7972) was the main ingredient in ELNs. It exerted stronger protective activities against LPS-induced acute lung inflammation than catalpol and acteoside, which are two well-known chemical markers in this herb. Moreover, miR-7972 decreased the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide (NO) in LPS-exposed RAW264.7 cells, thereby facilitating M2 macrophage polarization. Mechanically, miR-7972 downregulated the expression of G protein-coupled receptor 161 (GPR161), activating the Hedgehog pathway, and inhibited the biofilm form of Escherichia coli via targeting virulence gene sxt2. Therefore, miR-7972 derived from fresh R. Radix alleviated LPS-induced lung inflammation by targeting the GPR161-mediated Hedgehog pathway, recovering gut microbiota dysbiosis. It also provided a new direction for gaining novel bioactivity nucleic acid drugs and broadening the knowledge on cross-kingdom physiological regulation through miRNAs.
Display omitted
•Rgl-miR-7972 was the main ingredient in ELNs derived from fresh Rehmanniae Radix.•Rgl-miR-7972 improved LPS-induced inflammation via inhibiting GPR161.•Rgl-miR-7972 inhibited the biofilm form of Escherichia coli via inhibiting sxt2.•ELNs act as novel drug deliver for cross-kingdom physiological regulation.
Aims
The involvement of pyroptosis in ischemic stroke remains to be established. Therefore, we used the specific pyroptosis inhibitor Vx765 as an experimental intervention target in a murine model of ...stroke.
Methods
A total of 564 C57BL/6 mice were subjected to photothrombotic procedures and treated via gavage with Vx765 at 1‐hour post‐ischemia. We subsequently assessed the expression of Gasdermin D (GSDMD), inflammasomes, caspase‐1, and interleukin‐1β (IL‐1β) using immunofluorescence (IF) and Western blot (WB) analyses. We also examined ultrastructural changes of cortical neurons with transmission electron microscopy (TEM) and measured infarct volumes dynamically by magnetic resonance imaging (MRI). Moreover, we evaluated the neurologic deficits by modified neurological severity scores, the rotarod test, and Treadscan.
Results
Elevated expression of GSDMD and GSDMD p30, the pore‐forming subunit, was evident in the peri‐ischemic region on days one and three post‐ischemia. The neuronal plasma, nuclear, and mitochondrial membranes showed ultrastructural damage at day three post‐stroke. Elevated expression of inflammasomes, caspase‐1, and IL‐1β was also present on days one and three post‐injury. There were significant differences between Vx765‐treated and vehicle groups in mean infarct volumes (14.36 vs 21.52 mm3; 12.34 vs 18.56 mm3; 4.13 vs 10.06 mm3; P < .05 at day one, three, and seven post‐surgery, respectively). Mice treated with Vx765 showed better motor recovery as assessed by serial behavior tests and had better neuronal survival, which was attributable to pyroptosis inhibition, as illustrated by downregulated expression of the effector protein GSDMD, inflammasomes, caspase‐1, and IL‐1β. Besides, treatment with Vx765 preserved neuronal membrane structures after the ischemic injury.
Conclusions
Pyroptosis emerges as an important pathway for neuronal death in an acute ischemic stroke. Vx765, a low molecular weight drug that has proven safe in clinical epilepsy trials, has potential therapeutic value for cerebral ischemia by targeting the canonical inflammasome pathway of pyroptosis.
Aflatoxin B1 (AFB1), a mycotoxin contaminating food and feed, can trigger liver immune toxicity and threaten the poultry industry. Phillygenin (PHI) is a natural lignan derived primarily from ...Forsythia suspensa with hepatoprotective pharmacological and medicinal properties. This research aimed to investigate the preventive effects of PHI on the toxicity of AFB1 in the liver of chickens. Chickens were administered with AFB1 (2.8 mg/kg) and/or treated with PHI (24 mg/kg) for 33 days. The histopathological changes, serum biochemical indices, oxidative damage, inflammatory mediators, apoptosis, and activation of the NF-κB and Nrf2 signaling pathways were measured. Results revealed that dietary PHI ameliorated liver function indicators, reduced the malondialdehyde and inflammatory mediator production and the apoptotic cell number, and increased the antioxidant enzyme contents and Bcl-2 level. The quantitative realtime PCR and Western blot results revealed that PHI reduced p53, cytochrome c, Bax, caspase-9, and caspase-3 levels, normalized the NF-κB p65 phosphorylation, and upregulated the Nrf2 and its downstream genes expression in chicken liver. These results indicated that PHI has beneficial effects on AFB1-induced liver damage, oxidative damage, inflammatory response, apoptosis, and immunotoxicity by inhibiting NF-κB and activating the Nrf2 signaling pathway in chickens. This study provides new insight into the therapeutic uses of PHI.
Display omitted
•Phillygenin(PHI) ameliorates aflatoxin B1- induced liver damage in chicken.•PHI inhibits oxidative stress and inflammation in the AFB1-induced liver damage.•PHI reduces AFB1-induced hepatocytes apoptosis in the liver of chicken.•PHI alleviates AFB1 toxicity by the NF-κB and Nrf2 signaling pathways.
Scope
It remains unclear whether dietary advanced glycation end products (dAGEs)‐induced cognitive impairment is sex‐dependent. Trehalose may antagonize dAGEs‐induced neurotoxicity via glycogen ...synthase kinase‐3 beta (GSK3β)‐transcription factor EB (TFEB) signaling.
Methods and Results
The sex‐specific neurotoxicity of dAGEs and the protective role of trehalose are investigated both in vivo and in vitro. Both sexes of APP/PS1 mice are divided into three groups: that is, control, dAGEs, and dAGEs supplemented with trehalose. SHSY‐5Y cells incubated with AGE‐BSA and trehalose are also utilized. Dietary AGEs impair cognitive function only in female mice, which is restored by trehalose. Trehalose upregulates phosphorylated‐GSK3β serine9 (p‐GSK3β ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase‐48, estrogen receptor α and induces TFEB nuclear translocation in hippocampus, elevates IDE and ERβ in cortex, while reduces p‐tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p‐GSK3β ser9, induces TFEB nuclear translocation, consequently reverses AGE‐BSA‐induced tau phosphorylation in vitro.
Conclusions
Female mice are more susceptible to the deleterious effects of dAGEs on cognitive function, which may be owing to its regulation on ERβ. Trehalose can strongly reverse dAGEs‐induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK‐3β.
The sex‐specific neurotoxicity of dietary advanced glycation end products (dAGEs) and protection by trehalose were investigated both in vitro and in vivo. Female mice were more susceptible to the deleterious effects of dAGEs on cognitive function, which might be owing to its regulation on ERβ. Trehalose strongly reversed dAGEs‐induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK‐3β.
Chemotherapy‐induced neuropathic pain is a common dose‐limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole‐genome expression microarray ...and gene ontology analysis to identify the upregulation of a sequence‐specific DNA‐binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV‐SOX10‐EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1‐mediated promoter demethylation of SOX10 may contribute to oxaliplatin‐induced neuropathic pain.
What's new?
Neuropathic pain severely limits the use of oxaliplatin in cancer therapy, for reasons not fully understood. A possible mechanism underlying this phenomenon is the formation of platinum‐DNA crosslinks. This study describes a role for upregulation of the DNA‐binding protein HOXA6 in oxaliplatin‐induced neurotoxicity. In oxaliplatin‐treated rats, neuropathic pain was alleviated upon HOXA6 genetic disruption. TET1‐dependent demethylation of the SOX10 promoter was found to mediate HOXA6 upregulation. Based on previous studies in which HOXA6 downregulation exerted inhibitory effects in colorectal cancer, the present findings indicate that disruption of HOXA6 expression may ameliorate oxaliplatin‐induced neuropathic pain while also blocking tumor growth.
We detected disproportionate reports of premature ovarian insufficiency (POI) and related events, including amenorrhea, menstruation irregular, FSH increased, and premature menopause, following human ...papillomavirus (HPV) vaccine from FDA Vaccine Adverse Event Reporting System (VAERS). The signal was detected by the methods of Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS). When both methods detected a positive result, a signal was generated. Besides, time-scan map is drawn based on the IC value and 95%CI of BCPNN, if the IC curve showed a steady upward trend and the 95%CI narrowed, the signal was stable and strong association.The results showed that there were not POI reports of HPV vaccine, but VAERS received a total of 2, 389, 27 POI related events for HPV2, HPV4, HPV9 respectively from the year of marketed to 2018. No signal was detected for HPV2. HPV4-POI ralated events were all detected as signals by two methods. There was only one signal of menstruation irregular for HPV9. Time scan of HPV4-POI ralated events showed those signals were stability and strong association, but not for HPV9. Our results only represent statistical association between HPV vaccine and POI related events, causal relationship needs further investigation.
Objective
Clinical sepsis-associated biomarkers were utilized in a cecal ligation and puncture (CLP) septic mouse model to provide a reference for investigating pathophysiological mechanisms and ...evaluating novel therapeutic interventions for sepsis.
Methods
Sepsis in mice was induced by CLP, and clinical biomarkers were evaluated (survival rate, blood physiological and biochemical indices, cytokines, hepatorenal function parameters, and blood coagulation).
Results
The mortality rate was >70%. The body temperature, blood pressure, and heart rate decreased within 48 h. Low lactic acid was found at 8 h. The CLP mice showed typical inflammatory symptoms with decreased white blood cells and procalcitonin and increased levels of soluble triggering receptor expressed on myeloid cells-1, interleukin (IL)-6, IL-10, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, MIP-1β, and MIP-2. The platelet count and activated partial thromboplastin time significantly decreased, and the prothrombin time and prothrombin time–international normalized ratio markedly increased. Phenotypes of multiple organ dysfunction were found in the CLP model, including increased liver alanine aminotransferase and aspartate transaminase; significantly reduced total protein, globulin, and serum albumin; increased blood urea nitrogen and creatinine; and decreased blood glucose.
Conclusion
The clinical features of the CLP mouse model were similar to those of human patients with sepsis.
The sirtuin family in health and disease Wu, Qi-Jun; Zhang, Tie-Ning; Chen, Huan-Huan ...
Signal transduction and targeted therapy,
12/2022, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological ...processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.
A highly effective C-O coupling reaction of (hetero)aryl electrophiles with primary and secondary alcohols is reported. Catalyzed by a Ni
-aryl complex under long-wave UV (390-395 nm) irradiation in ...the presence of a soluble amine base without any additional photosensitizer, the reaction enables the etherification of aryl bromides and aryl chlorides as well as sulfonates with a wide range of primary and secondary aliphatic alcohols, affording synthetically important ethers. Intramolecular C-O coupling is also possible. The reaction appears to proceed via a Ni
-Ni
catalytic cycle.
Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority ...goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71, p = 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79, p = 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.
PDF
