ETHNOPHARMACOLOGICAL RELEVANCE:Dendrobium officinale Kimura et Migo (D. officinale), a rare and precious orchid (Orchidaceae) in traditional Chinese medicine, exhibits a sweet flavor and a cold nature, and acts on lung, stomach, and kidney meridians with marked efficacy in nourishing lung yin. When applied medicinally and in functional foods, it demonstrates antioxidant, immunomodulatory, anti-inflammatory, and anti-inflammatory, and antitumor bioactivities. AIM OF THE STUDY:This study aimed to investigate the role and mechanisms of action of an ethyl acetate extract of D. officinale (DOEA) in the treatment of acute lung injury (ALI). MATERIALS AND METHODS:The pharmacological effects of DOEA extract were evaluated using lipopolysaccharide (LPS)-induced ALI models in vivo and RAW264.7 cell models in vitro. Transcriptomic profiling was performed via RNA sequencing to elucidate the mechanism by which DOEA protects against LPS-induced injury. ALI Furthermore, the protective effects of DOEA against LPS-induced ALI and cellular inflammatory responses were comprehensively evaluated through histology, lung index assessment, immunofluorescence, immunohistochemistry, Western blotting, quantitative real-time PCR, and flow cytometry. Exploring the anti-inflammatory effects of DOEA on the IL-17A signaling pathway was achieved by knocking down IL-17RA in RAW264.7 cells via siRNA interference technology, as well as by conducting exogenous IL-17A stimulation experiments. RESULTS:DOEA mitigated LPS-induced ALI by attenuating pulmonary cytokine expression, suppressing NF-κB pathway activation, and reducing oxidative tissue damage via the inhibition of cellular oxidative stress. Moreover, the efficacy of DOEA against ALI was significantly associated with the targeting of IL-17RA. Notably, IL-17RA knockdown significantly alleviated the LPS-induced inflammatory response in RAW264.7 cells. Furthermore, DOEA was able to suppress the inflammatory response induced by exogenous IL-17A stimulation in these cells. CONCLUSION:DOEA alleviates LPS-induced acute lung injury and cellular inflammatory responses by inhibiting the IL-17 signaling pathway.

A bioassay-guided phytochemical investigation on the ethyl acetate extract from the roots of Lindera aggregata (Sims) Kosterm led to the isolation of fifteen sesquiterpenoids, comprising twelve previously undescribed compounds, linderasins A-L (1-12), and three known analogues (13-15). Their structures were elucidated by comprehensive spectroscopic analyses, quantum chemical calculations, and single-crystal X-ray diffraction. Notably, compounds 1 and 2 were unusual homolindenane sesquiterpenoids bearing an additional carbon at C-11 in 1 and C-8 in 2, while compounds 3 and 11 were 12,13-bisnorlindenane and 15-noreudesmane sesquiterpenoids, respectively. Compounds 13-15 were isolated for the first time from a plant of the order Laurales. All isolates were evaluated for their anti-inflammatory activity in lipopolysaccharide-stimulated RAW264.7 macrophages. In a preliminary screening, compounds 2, 3, 7, and 10 showed moderate inhibition of nitric oxide (NO) production without significant cytotoxicity. Further RT-qPCR analysis revealed that compound 10 dose-dependently downregulated the mRNA expression of key inflammatory mediators, including IL-1β, IL-6, iNOS, and COX-2. Collectively, this study expanded the chemical diversity of sesquiterpenoids from L. aggregata and identified compound 10 as a promising anti-inflammatory lead that merits further mechanistic and in vivo investigation.

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic metabolic disease that severely affects human health. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) is a mixture rich in diverse natural flavonoids that exhibits multiple pharmacological properties, including significant anti-inflammatory and antioxidant activities. However, the anti-MASH effects of QFAEE and the underlying mechanisms remain unknown. This study aimed to investigate the therapeutic effects of QFAEE on MASH and the related mechanisms. The therapeutic effects of QFAEE on hepatic steatosis, inflammatory responses, oxidative stress and apoptotic activity were systematically evaluated in both in vivo and in vitro models of metabolic stress. QFAEE administration significantly reduced hepatic lipid accumulation, inflammatory cell infiltration and liver injury in HFHC diet-fed mice. Combined RNA sequencing and network pharmacology analyses revealed that QFAEE exerted its anti-MASH effects through modulation of the PPAR signaling pathway. QFAEE ameliorated MASH by activating PPARα and subsequently upregulating CPT1A, which promoted mitochondrial and peroxisomal β-oxidation. Notably, PPARα inhibition promoted hepatic lipid accumulation, inflammation and oxidative stress in hepatocytes, all of which were significantly attenuated by QFAEE treatment. These findings suggest that QFAEE prevents metabolic stress-induced MASH progression by activating PPARα signaling.

Previous studies have shown that Quzhou Fructus Aurantii extract (QFAEE) ameliorates lipopolysaccharide (LPS)-induced acute lung injury (ALI) by modulating the Stimulator of interferon genes (STING) pathway. Nevertheless, the mechanisms underlying the anti-inflammatory effects of nobiletin (Nob), the primary bioactive component of QFAEE, have not been clearly elucidated. The present study aimed to investigate the protective effects of Nob on a mouse model of LPS-induced ALI and elucidate its underlying mechanism. The pulmonary inflammatory response in mice was quantified by performing fluorescence-based RT‒qPCR, bronchoalveolar lavage fluid (BALF) cell counting, and hematoxylin‒eosin (HE) staining. Transcriptomic profiling was performed to explore the mechanisms by which Nob ameliorates LPS-induced ALI. The anti-inflammatory mechanisms were further elucidated using western blotting, immunohistochemical staining, cellular thermal shift assays (CETSAs), and microscale thermophoresis. Functional validation was conducted using the STING agonist vadimezan (DMXAA), the STING inhibitor SN-001, and STING-knockout (STING-KO) mice. Nobiletin-loaded liposomes (Nob-Lipo) significantly attenuated LPS-induced pulmonary inflammation in mice. The results of the transcriptomic analysis suggested that this protective effect was associated with the modulation of the type I interferon pathway. In RAW264.7 and THP-1 cells, pretreatment with Nob effectively attenuated the interferon regulatory factor 3 (IRF3)-mediated type I interferon response and nuclear factor kappa-B (NF-κB)-dependent proinflammatory cytokine expression following DMXAA-induced STING pathway activation. Furthermore, the STING inhibitor SN‑001 markedly suppressed LPS‑induced inflammatory responses, as evidenced by significantly reduced levels of proinflammatory cytokines and interferon‑stimulated genes, and effectively blocked the nuclear translocation of NF‑κB and IRF3. Notably, after inhibitor treatment, Nob no longer exerted its previously observed anti‑inflammatory effects, further supporting the critical regulatory role of STING in LPS‑mediated inflammation and indicating that the anti‑inflammatory activity of Nob is primarily dependent on the STING pathway. Moreover, in STING‑KO mice with LPS‑induced ALI, the loss of the protective effect of Nob further confirmed that its anti‑inflammatory activity depends on STING, highlighting the essential role of STING signaling in mediating its protective effects. In conclusion, the protective effect of Nob on an LPS-induced ALI model is mediated primarily through the modulation of STING signaling.

Currently, limited research exists on the relationship between osteoarthritis (OA) and Benzophenone-3 (BP-3). This study aims to explore the potential molecular pathways involved, using both in vivo and in vitro biological experiments. In vivo experiments revealed that exposure to BP-3 leads to cartilage damage in the knee joints of rats, suggesting that BP-3 may be a significant risk factor in the development and progression of osteoarthritis. Proteomic sequencing of knee cartilage tissue revealed alterations in multiple inflammatory pathways in the BP-3 group. In vitro cellular experiments further demonstrated the toxic effects of BP-3 on chondrocytes, including inflammatory changes and increased transcriptional levels of IL-6. Cellular transcriptomics sequencing revealed significant changes in multiple intracellular inflammatory pathways, particularly the JAK-STAT pathway. Additional experiments demonstrated that BP-3 enhances STAT3 phosphorylation, promoting the degradation of extracellular matrix (ECM) proteins. Silence of STAT3 alleviated the impaired effects of BP-3 on chondrocytes. Overall, our data suggest that BP-3 exposure may be a significant risk factor for OA development. This study provides substantial evidence and a comprehensive understanding of the impact of BP-3 on OA development.

Background:Viral pneumonia is the most common and lethal pandemic disease, but there are no broad-spectrum antiviral drugs with high genetic barriers to resistance. To elucidate the mechanisms of viral pneumonia progression and potential targets for its treatment. Methods:Viral pneumonia models were induced by the PR8 virus strain in wild-type (WT) and STING knockout (STING-KO) mice. Series of molecular biology techniques were used to evaluate the severity of pneumonia and cytokine levels. Results:In this study, STING (stimulator of interferon genes) was activated in the lungs of virus-infected mice, leading to cytokine production and amplification of the immune response, thereby causing rapid deterioration of symptoms. Furthermore, excessive activation of innate immune response via STING was prevented by a STING inhibitor (C-176), which significantly reduced viral lung inflammation. The formation of neutrophil extracellular traps (NETs) was similarly suppressed during viral pneumonia treatment with STING inhibitors (C-176), and NETs formation and STING expression were positively correlated, indicating that STING plays an important role in NETs formation. Symptoms of pneumonia in STING-KO mice infected with PR8 were significantly milder than those in WT mice, and NETs were less likely to form in the lung tissue of STING-KO mice. Additionally, transcriptomic analysis revealed that STING-mediated regulation of NETs may be associated with gasdermin D (GSDMD), and immunoprecipitation experiments revealed that STING, GSDMD, and NETs-related proteins interact with each other. Immunofluorescence assays revealed that in neutrophils from WT mice, STING and GSDMD were colocalized on the membrane after viral infection, whereas in neutrophils from STING-KO mice, GSDMD expression was decreased after exposure to the virus. Conclusions:Our study demonstrated that targeted intervention with STING alleviated pneumonia by inhibiting inflammation and NETs formation. The study also revealed that blocking STING could inhibit the activation of GSDMD to inhibit NETs formation, slowing the progression of viral pneumonia.

Background:Acute lung injury (ALI), a critical respiratory condition, often escalates into acute respiratory distress syndrome, which is associated with significant morbidity and mortality. Bauhinia championii, a botanical drug used in traditional Chinese medicine, is reputed for its antioxidative and anti-hypoxia effects. However, the active metabolites within B. championii and their mechanisms of action in alleviating ALI remain to be elucidated. Methods:A comprehensive literature review and database search within Chemistry Database were conducted to compile a complete profile of the metabolites identified in B. championii. Utilizing network analysis, we predicted potential targets of metabolites in B. championii (MBC) for ALI treatment. A protein-protein interaction (PPI) network was constructed using Cytoscape 3. 9. 1, complemented by GO annotations and KEGG pathway enrichment analyses via the DAVID online platform. The isolation and characterization of polymethoxyflavones (PMFs) from B. championii were performed using HPLC and confirmed by LC-MS. In vivo pharmacological assessments were executed to substantiate the network analysis predictions. Moreover, the Autodock software facilitated molecular docking studies to elucidate the role of endoplasmic reticulum (ER) stress modulation in ALI treatment by PMFs. Results:17 known MBC were identified in which 7 active metabolites of flavonoids were used as predictive targets. 122 target genes associated with both MBC and ALI were tested for KEGG and GO enrichment analyses, which indicated these target genes involvement in antioxidant, anti-inflammatory, and anti-apoptotic pathways. The PMFs were extracted from B. championii and identified as 5, 6, 7, 3', 4'-pentamethoxyflavone, 5, 6, 7, 3', 4', 5'-hexamethoxyflavone, 5, 7, 3', 4', 5'-pentamethoxyflavone, 5, 6, 7, 5'-tetramethoxy-3', 4'-methylenedioxyflavone and 5, 7, 5'-trimethoxy-3', 4'-methylenedioxyflavone. PMFs were effective in alleviating LPS-induced pulmonary inflammatory responses for releasing ALI. In addition, PMFs inhibited the secretion of GSH-Px and CAT, reduced the accumulation of HYP and MDA as well as the infiltration of inflammatory cells, not to mention alleviated LPS-induced apoptosis by inhibiting the Caspase 3-mediated apoptosis pathway. Furthermore, the PMFs can spontaneously bind to multiple ER stress targets to exert the effect of calming ER stress to alleviate ALI. Conclusion:PMFs inhibited the expression of inflammatory cytokines and reduced oxidative stress injury to resist apoptosis in lung. Moreover, PMFs attenuated LPS-induced ER stress activation by regulating ER stress related targets, which in turn alleviated ALI.

Background: Viral pneumonia is an infection of the lungs caused by numerous different viruses, which can lead to severe respiratory distress and even life-threatening conditions. In the absence of specific treatments for viral pneumonia, natural traditional medicines offer an alternative in terms of innovative drug therapies. Morus alba L. (common name mulberry leaf) is a Chinese medicine that has been used clinically as an antiviral. Purpose: The therapeutic effect of M. alba on viral pneumonia was investigated along with its mechanism of action. Methods: Network pharmacology and molecular docking were used to analyze the mechanism of action of M. alba in the treatment of viral pneumonia. Histology, immunofluorescence, Western blotting, qPCR, and flow cytometry were used to evaluate the protective effect of MLE (the ethanol extract of Morus alba L.) on PR8 (A/ Puerto Rico/8/1934 H1N1, a murine lung-adapted influenza A virus strain)-induced viral pneumonia. SiRNA was used to validate the relationship between the therapeutic effects of MLE on viral pneumonia and the target Syk (a crucial non-receptor tyrosine kinase). Results: MLE alleviated PR8-induced viral pneumonia by reducing inflammatory factor expression in the lungs, decreasing NF-kappa B pathway activation, slowing oxidative damage in the lungs, and inhibiting lung tissue cell apoptosis. Meanwhile, MLE for viral pneumonia was significantly associated with Syk targets. Notably, knockdown of the Syk gene not only reduced the therapeutic effect of MLE, but also suppressed PR8-induced viral pneumonia. Conclusion: MLE can alleviate PR8-induced viral pneumonia through inhibiting the Dectin-1/Syk pathway.

The aim of this study is to conduct a thorough evaluation of the association between Benzophenone-3 (BP-3) exposure and OA, offering critical insights into the underlying mechanisms involved. The National Health and Nutrition Examination Survey (NHANES) database was utilized to investigate the correlation between BP-3 and osteoarthritis. Proteomic sequencing from clinical sample and the PharmMapper online tool were employed to predict the biological target of BP-3. Cellular molecular assays and transfection studies were performed to verify the prediction from bioinformatics analyses. Through cross-sectional analysis of the NHANES database, we identified BP-3 as a risk factor for OA development. The results of proteomic sequencing showed that Secreted Protein Acidic and Rich in Cysteine (SPARC) was significantly elevated in the area of damage compared to the undamaged area. SPARC was also among the potential biological targets of BP-3 predicted by the online program. Through in vitro cell experiments, we further determined that the toxicological effects of BP-3 may be due to SPARC, which elevates intracellular GPX4 levels, activates the glutathione system, and promotes lipid peroxidation to mitigate ferroptosis. Inhibiting SPARC expression has been shown to reduce inflammation and ferroptosis in OA contexts. This research provides an expansive understanding of BP-3's influence on osteoarthritis development. We have identified SPARC as a potent target for combating chondrocyte ferroptosis in BP-3-associated osteoarthritis.

Background: Acute respiratory distress syndrome (ARDS) is an acute respiratory disease characterized by bilateral chest radiolucency and severe hypoxemia. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE), which is prepared from the traditional Chinese respiratory anti-inflammatory natural herb Quzhou Fructus Arantii, has the potential to alleviate ARDS. In this work, we aimed to investigate the potential and mechanism underlying the action of QFAEE on ARDS and how QFAEE modulates the STING pathway to reduce type I interferon release to alleviate the inflammatory response. Methods: Lipopolysaccharide (LPS), a potential proinflammatory stimulant capable of causing pulmonary inflammation with edema after nasal drops, was employed to model ARDS in vitro and in vivo. Under QFAEE intervention, the mechanism of action of QFAEE to alleviate ARDS was explored in this study. TREX1-/- mice were sued as a research model for the activation of the congenital STING signaling pathway. The effect of QFAEE on TREX1- /- mice could explain the STING-targeted effect of QFAEE on alleviating the inflammatory response. Our explorations covered several techniques, Western blot, histological assays, immunofluorescence staining, transcriptomic assays and qRT-PCR to determine the potential mechanism of action of QFAEE in antagonizing the inflammatory response in the lungs, as well as the mechanism of action of QFAEE in targeting the STING signaling pathway to regulate the release of type I interferon. Results: QFAEE effectively alleviates ARDS symptoms in LPS-induced ARDS. We revealed that the mechanism underlying LPS-induced ARDS is the STING-TBK1 signaling pathway and further elucidated the molecular mechanism of QFAEE in the prevention and treatment of ARDS. QFAEE reduced the release of type I interferons by inhibiting the STING-TBK1-IRF3 axis, thus alleviating LPS-induced pneumonia and lung cell death in mice. Another key finding is that activation of the STING pathway by activators or targeted knockdown of the TREX1 gene can also induce ARDS. As expected, QFAEE was found to be an effective protective agent in alleviating ARDS and the antagonistic effect of QFAEE on ARDS was achieved by inhibiting the STING signaling pathway. Conclusions: The main anti-inflammatory effect of QFAEE was achieved by inhibiting the STING signaling pathway and reducing the release of type I interferons. According to this mechanism of effect, QFAEE can effectively alleviate ARDS and can be considered a potential therapeutic agent. In addition, the STING pathway plays an essential role in the development and progression of ARDS, and it is a potential target for ARDS therapy.

Given the escalating severity of colitis caused by Salmonella infection and the growing challenge of drug resistance, there is an urgent demand for novel and effective treatment strategies with minimal side effects. Herein, we explored the potential therapeutic effects of polysaccharides on Ulcerative Colitis (UC). Our results showed that both purified polysaccharide from Dendrobium devonianum (DVP-1) and Crude polysaccharides from Dendrobium devonianum (CP) pre-treatment could prevent colon shortening and spleen enlargement, and alleviate colonic tissue damage. Western blot and RT-qPCR analyses revealed that DVP-1 and CP downregulated pro-inflammatory mediators while upregulating the expression of the anti-inflammatory mediator and tight junction proteins. Besides, 16S rRNA sequencing analysis showed that DVP-1 modulated gut dysbiosis by increasing the relative abundance of ClostridiumXlVa, and reducing the relative abundance of Alloprevotella. Additionally, DVP-1 and CP significantly increased the concentrations of tryptophan metabolites while decreasing purine metabolites. Taken together, these findings suggest that DVP-1 and CP yield potential benefits in alleviating UC primarily through restoring intestinal barrier function and regulating intestinal microbiota.

Heat exposure induces excessive hyperthermia associated with systemic inflammatory response that leads to multiple organ dysfunction including acute lung injury. However, how heat impairs the lung remains elusive so far. We aimed to explore the underlying mechanism by focusing on leucine-rich repeat kinase 2 (LRRK2), which was associated with lung homeostasis. Both in vivo and in vitro models were induced by heat exposure. Firstly, heat exposure exerted core temperature (Tc) disturbance, pulmonary dysfunction, atelectasis, inflammation, impaired energy metabolism, and reduced surfactant proteins in the lung of mice. In addition, decreased LRRK2 expression and increased heat shock proteins (HSPs) 70 were observed with heat exposure in both the lung of mice and alveolar type II epithelial cells (AT2). Furthermore, LRRK2 inhibition aggravated heat exposure-initiated Tc dysregulation, injury in the lung and AT2 cells, and enhanced HSP70 expression. In conclusion, LRRK2 is involved in heat-induced acute lung injury and AT2 cell dysfunction.

Ethnopharmacological relevance: Pulmonary fibrosis (PF) is an irreversible lung disease that severely affects human respiratory function. Traditionally, the natural plant Quzhou Fructus Arantii (QFA) has therapeutic effects on respiratory diseases. However, the effects and the mechanism of anti-fibrotic have not been elucidated.Aim of the study: In this study, QFAE-nB was extracted from QFA, the aims of this study include understanding the correlation between Bleomycin (BLM)-induced PF and STING pathway in mice, as well as exploring the role and mechanisms of QFAE-nB in the treatment of PF. Materials and methods: QFAE-nB was extracted from QFA, six main chemical components in QFAE-nB were identified by HPLC-QTOF-MS/MS, and quantitative analysis was conducted by HPLC. qPCR and Western blot were used to verify the molecular mechanism of QFAE-nB, and the anti-fibrotic effect of QFAE-nB was deter-mined by hematoxylin-eosin (HE) staining and Masson staining as well as immunohistochemistry. TREX1-KO and STING-KO mice were used to verify the relationship between STING and PF and the important target action of QFAE-nB.Results: Six main flavonoids in QFAE-nB were identified as eriocitrin (0.76%), neoeriocitrin (2.79%), narirutin (4.31%), naringin (35.41%), hesperidin (1.74%), and neohesperidin (27.18%). The results showed that BLM-induced PF was associated with its exacerbated release of proinflammatory factors and chemokines in lung tissues. In addition, QFAE-nB alleviated BLM-induced lung fibrosis in mice by inhibiting the activation of the STING signaling pathway and reducing the signal transduction of TBK1-IRF3 and TBK1-NF-kappa B pathways. Notably, knockout of the TREX1 gene caused massive inflammation and even induced PF in the lung tissues, whereas QFAE-nB effectively alleviated inflammation and reduced PF. The deletion of the STING gene sup-pressed BLM-induced PF and inflammation, but STING-KO mice treated with QFAE-nB showed even lower expression levels of proinflammatory factors and chemokine.Conclusions: The STING pathway plays an important role in PF, and QFAE-nB alleviates PF by mainly targeting the inhibition of the STING pathway to reduce inflammation. Together, the study paves the way for targeting the STING pathway in PF treatment.

The broad-spectrum antineoplastic drug doxorubicin (DOX) has one of the most serious chronic side effects on the heart, dilated cardiomyopathy, but the precise molecular mechanisms underlying disease progression subsequent to long latency periods remain puzzling. Here, we established a model of DOX-induced dilated cardiomyopathy. In a cardiac cytology exploration, we found that differentially expressed genes in the KEGG signaling pathway enrichment provided a novel complex network of mTOR bridging autophagy and oxidative stress. Validation results showed that DOX caused intracellular reactive oxygen species accumulation in cardiomyocytes, disrupted mitochondria, led to imbalanced intracellular energy metabolism, and triggered cardiomyocyte apoptosis. Apoptosis showed a negative correlation with DOX-regulated cardiomyocyte autophagy. To evaluate whether the inhibition of mTOR could upregulate autophagy to protect cardiomyocytes, we used rapamycin to restore autophagy depressed by DOX. Rapamycin increased cardiomyocyte survival by easing the autophagic flux blocked by DOX. In addition, rapamycin reduced oxidative stress, prevented mitochondrial damage, and restored energy metabolic homeostasis in DOX-treated cardiomyocytes. In vivo, we used metformin (Met) which is an AMPK activator to protect cardiac tissue to alleviate DOX-induced dilated cardiomyopathy. In this study, Met significantly attenuated the oxidative stress response of myocardial tissue caused by DOX and activated cardiomyocyte autophagy to maintain cardiomyocyte energy metabolism and reduce cardiomyocyte apoptosis by downregulating mTOR activity. Overall, our study revealed the role of autophagy and apoptosis in DOX-induced dilated cardiomyopathy and demonstrated the potential role of regulation of the AMPK/mTOR axis in the treatment of DOX-induced dilated cardiomyopathy.

The black-necked crane is the only species of crane that lives in the high-altitude region of the Tibet Plateau. At present, there is little research on viral diseases of the black-necked crane (Grus nigricollis). In this study, a viral metagenomic approach was employed to investigate the fecal virome of black-necked cranes in Saga County, Shigatse City, Tibet, China. The identified virus families carried by black-necked cranes mainly include Genomoviridae, Parvoviridae, and Picornaviridae. The percentages of sequence reads belonging to these three virus families were 1.6%, 3.1%, and 93.7%, respectively. Among them, one genome was characterized as a novel species in the genus Grusopivirus of the family Picornaviridae, four new parvovirus genomes were obtained and classified into four different novel species within the genus Chaphamaparvovirus of the subfamily Hamaparvovirinae, and four novel genomovirus genomes were also acquired and identified as members of three different species, including Gemykroznavirus haeme1, Gemycircularvirus ptero6, and Gemycircularvirus ptero10. All of these viruses were firstly detected in fecal samples of black-necked cranes. This study provides valuable information for understanding the viral community composition in the digestive tract of black-necked cranes in Tibet, which can be used for monitoring, preventing, and treating potential viral diseases in black-necked cranes.

Diabetic nephropathy (DN), which is characterized by renal fibrosis, is a major complication of diabetes, a disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis is an essential signaling pathway in DN-related injuries, such as renal fibrosis. Pyrroloquinoline quinone (PQQ) is a naturally occurring bioactive compound that protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused by high glucose concentrations. However, the nature and underlying mechanism of the effect of PQQ on DN-related renal fibrosis remains unclear. In this study, we evaluated whether PQQ has potential protective effects against renal fibrosis due to DN by establishing type 1 diabetes in mice via streptozotocin treatment and then inhibiting their pyroptosis signaling pathway. We found that compared to control mice, the area of renal fibrosis and injury were significantly increased in diabetic mice, and this was accompanied by increased levels of expression of collagen I and transforming growth factor-beta 1; increased concentrations of the inflammatory cytokines, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha; and activation of the pyroptosis pathway components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1 beta, and IL-18. All of these changes were reversed by PQQ treatment. Analogously, we treated cultured HK-2 cells with a high concentration of glucose (35 mmol/L), which caused these cells to exhibit significantly increased concentrations of reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-kappa B), p-IkappaB, NLRP3, caspase-1, IL-1 beta, and IL-18, and the loss of mitochondrial transmembrane potential. However, PQQ treatment significantly blunted these effects. In conclusion, in this study we demonstrated that PQQ attenuates renal fibrosis by alleviating mitochondrial dysfunction, reducing ROS production, and inhibiting the activation of the NF-kappa B/pyroptosis pathway under conditions of DN and hyperglycemia.

BACKGROUND:CHMP1A, a member of the ESCRT-III complex family, has been indicated as a brand-new inhibitor gene of tumors. Our previous research has revealed that CHMP1A plays a vital role in the development and progression of renal cell carcinoma (RCC).OBJECTIVE:To investigate the potential target pathway of the regulation of the tumor cell growth by CHMP1A.METHODS:The effect of CHMP1A on mTOR pathway was elucidated by western blotting. The effect of CHMP1A on the expression of p53 was evaluated, and A498 cell growth was assessed by colony formation and MTT assays. The expression of p53 was knocked down by shRNA-p53, and the effect of CHMP1A on mTOR after knockdown of p53 was evaluated. The effect of CHMP1A on apoptosis and its relationship with MDM2 pathway were detected by western blotting and FCM. Finally, the relationship between the regulation of p53 by CHMP1A and the PI3K/mTOR pathway was detected.RESULTS:This study showed that the mTOR pathway was suppressed significantly in CHMP1A-overexpressing A498 and 786-0 cells; moreover, the enhanced expression of p53 and the reduced proliferation were shown in CHMP1A-overexpressing A498 cells. Furthermore, CHMP1A was able to regulate the PI3K/PTEN/mTOR and MDM2/p53 pathways in order to suppress RCC. In addition, CHMP1A regulated Bax and Bcl-2 via MDM2/p53 to induce the apoptosis of tumor cells and upregulated the expression of p53 via the PI3K/mTOR pathway.CONCLUSIONS:The results convey that CHMP1A-related suppression of RCC is closely related to the PI3K/mTOR/p53 pathway.

目的 研究人参不定根(ginseng adventitious roots,GAR)提取物对异丙肾上腺素(isoproterenol,ISO)诱导的小鼠心肌缺血损伤的保护作用.方法 50只C57BL/6小鼠随机分为5组(n=10),包括对照组、ISO组、低剂量GAR+ISO组,高剂量GAR+ISO组、高剂量GAR组,连续灌胃28 d,在第27、28 d皮下注射ISO建立小鼠心肌缺血模型(对照组与高剂量GAR组注射同剂量生理盐水).检测小鼠体重、心重、心重体重比和心电图变化,苏木精—伊红染色法染色检测心脏组织病理学改变,试剂盒检测心肌损伤相关酶及抗氧化相关酶活性,蛋白质印迹法检测炎症相关蛋白半胱天冬酶-1(caspase-1)及白介素-1β(interleukin-1,IL-1β)表达变化.结果 GAR预保护显著降低ISO导致的ST段升高和心重体重比增加,降低血清中心肌损伤相关酶乳酸脱氢酶、肌酸激酶同工酶、谷丙转氨酶和心肌肌钙蛋白T水平,明显提高心肌组织抗氧化相关酶超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶活性.组织病理学分析也显示GAR能够减轻心肌损伤,通过蛋白质印记分析发现GAR明显减少炎症通路caspase-1、IL-1β蛋白表达.通过相同实验检测高剂量GAR组对正常机体组织病理及各类生化指标无任何明显损伤作用.结论 GAR对ISO导致的心脏损伤具有明显的保护作用,其机制可能是增强内源性抗氧化能力及减少炎症蛋白表达.

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1β, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.

Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.