Diagnosis, toxicological mechanism, and detoxification for hepatotoxicity induced by pyrrolizidine alkaloids from herbal medicines or other plants.

Pyrrolizidine alkaloids (PAs) are one type of phytotoxins distributed in various plants, including many medicinal herbs. Many organs might suffer injuries from the intake of PAs, and the liver is the most susceptible one. The diagnosis, toxicological mechanism, and detoxification of PAs-induced hepatotoxicity have been studied for several decades, which is of great significance for its prevention, diagnosis, and therapy. When the liver was exposed to PAs, liver sinusoidal endothelial cells (LSECs) loss, hemorrhage, liver parenchymal cells death, nodular regeneration, Kupffer cells activation, and fibrogenesis occurred. These pathological changes classified the PAs-induced liver injury as acute, sub-acute, and chronic type. PAs metabolic activation, mitochondria injury, glutathione (GSH) depletion, inflammation, and LSECs damage-induced activation of the coagulation system were well recognized to play critical roles in the pathological process of PAs-induced hepatotoxicity. A lot of natural compounds like glycyrrhizic acid, (-)-epicatechin, quercetin, baicalein, chlorogenic acid, and so on were demonstrated to be effective in alleviating PAs-induced liver injury, which rendered them huge potential to be developed into therapeutic drugs for PAs poisoning in clinics. This review presents updated information about the diagnosis, toxicological mechanism, and detoxification studies on PAs-induced hepatotoxicity.

Analysis of Correlation Between Serum Hypoxia-Inducible Factor-1α, Uric Acid, and Inflammatory Factor Levels and Lung Function in Patients with AECOPD.

Objective: To investigate the correlation between the serum hypoxia-inducible factor-1α, uric acid, inflammatory factor levels, and lung function in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: The clinical data of patients with chronic obstructive pulmonary disease (40 cases) from March 2020 to March 2021 were retrospectively analyzed. According to the disease condition in patients with chronic obstructive pulmonary disease, they were divided into acute exacerbation stage (observation group, 20 cases) and stable stage (control group, 20 cases). All patients' basic data such as age, sex, and course of disease were collected and sorted out, and the serum hypoxia-inducible factor-1α, uric acid, inflammatory factor levels (procalcitonin, interleukin-6, and high-sensitivity C-reactive protein), and the index of their pulmonary function were measured. The profiles of serum hypoxia-inducible factor-1 alpha and uric acid, levels of inflammatory factors, and pulmonary function indices were measured and compared between the observation and control groups. The correlation between patients' serum hypoxia-inducible factor-1α, uric acid, and inflammatory factors and lung function was analyzed. Results: There was no difference in basic data between the observation group and the control group, P > .05. Serum hypoxia-inducible factor-1α, uric acid, and levels of inflammatory factors were all higher in the observation group than the control group, and the differences are significant (P < .05). There was significant difference in lung function indexes between the observation group and the control group (P < .05). Serum hypoxia-inducible factor-1α, uric acid, and inflammatory factor levels were negatively associated with pulmonary function indices. Conclusion: The more serious the condition of AECOPD patients is, the levels of serum hypoxia inducible factor -1α, uric acid and inflammatory factors gradually increase, and the lung function tends to decline.

[Discovery of miRNA and target signal molecules involved in inhibition of chlorogenic acid on N-acetyl-p-aminophenol-induced hepatotoxicity based on microRNA array].

This study aims to observe the effect of chlorogenic acid(CGA) on microRNA(miRNA) in the process of protecting against N-acetyl-p-aminophenol(APAP)-induced liver injury. Eighteen C57BL/6 mice were randomly assigned into a normal group, a model group(APAP, 300 mg·kg~(-1)), and a CGA(40 mg·kg~(-1)) group. Hepatotoxicity of mice was induced by intragastric administration of APAP(300 mg·kg~(-1)). The mice in the CGA group were administrated with CGA(40 mg·kg~(-1)) by gavage 1 h after APAP administration. The mice were sacrificed 6 h after APAP administration, and plasma and liver tissue samples were collected for the determination of serum alanine/aspartate aminotransferase(ALT/AST) level and observation of liver histopathology, respectively. MiRNA array combined with real-time PCR was employed to discover important miRNAs. The target genes of miRNAs were predicted via miRWalk and TargetScan 7.2, verified by real-time PCR, and then subjected to functional annotation and signaling pathway enrichment. The results showed that CGA administration lowered the serum ALT/AST level elevated by APAP and alleviate the liver injury. Nine potential miRNAs were screened out from the microarray. The expression of miR-2137 and miR-451a in the liver tissue was verified by real-time PCR. The expression of miR-2137 and miR-451a was significantly up-regulated after APAP administration, and such up-regulated expression was significantly down-regulated after CGA administration, consistent with the array results. The target genes of miR-2137 and miR-451a were predicted and verified. Eleven target genes were involved in the process of CGA protecting against APAP-induced liver injury. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment with DAVID and R language showed that the 11 target genes were enriched in Rho protein-related signal transduction, vascular patterning-related biological processes, binding to transcription factors, and Rho guanyl-nucleotide exchange factor activity. The results indicated that miR-2137 and miR-451a played an important role in the inhibition of CGA on APAP-induced hepatotoxicity.

Chlorogenic acid ameliorated non-alcoholic steatohepatitis via alleviating hepatic inflammation initiated by LPS/TLR4/MyD88 signaling pathway.

Non-alcoholic steatohepatitis (NASH) is a severe pathological stage in non-alcoholic fatty liver disease (NAFLD) and is generally recognized to be induced by chronic inflammation. Natural compound chlorogenic acid (CGA) is well-known for its anti-inflammatory capacity. This study aimed at evaluating the alleviation of CGA on NASH and further exploring its engaged mechanism via focusing on abrogating hepatic inflammation. Our results showed that CGA had a good amelioration on NASH in vivo. CGA alleviated liver oxidative injury by inducing nuclear factor erythroid 2-related factor 2 (Nrf2) activation and reduced liver steatosis via up-regulating peroxisome proliferator-activated receptor-alpha (PPARα). CGA attenuated hepatic inflammation in vivo, but didn't decrease the elevated lipopolysaccharide (LPS) content. CGA blocked the activation of nuclear factor kappa-B (NFκB) or inflammasome both in MCDD-fed mice and in LPS-stimulated macrophages. CGA was found to directly bind to myeloid differentiation primary response 88 (MyD88), and thus competitively blocked the interaction between toll-like receptor 4 (TLR4) and MyD88, thereby abrogating hepatic inflammation initiated by LPS-TLR4-MyD88. Moreover, the CGA-provided anti-inflammatory effect was obviously disappeared in macrophages overexpressed MyD88. Hence, CGA has an excellent efficacy in improving NASH. CGA alleviated liver inflammation during NASH progression through blocking LPS-TLR4-MyD88 signaling pathway via directly binding to MyD88.

EGR1 is crucial for the chlorogenic acid-provided promotion on liver regeneration and repair after APAP-induced liver injury.

Improper use of acetaminophen (APAP) will induce acute liver failure. This study is designed to investigate whether early growth response-1 (EGR1) participated in the promotion on liver repair and regeneration after APAP-induced hepatotoxicity provided by natural compound chlorogenic acid (CGA). APAP induced the nuclear accumulation of EGR1 in hepatocytes regulated by extracellular-regulated protein kinase (ERK)1/2. In Egr1 knockout (KO) mice, the liver damage caused by APAP (300 mg/kg) was more severe than in wild-type (WT) mice. Results of chromatin immunoprecipitation and sequencing (ChIP-Seq) manifested that EGR1 could bind to the promoter region in Becn1, Ccnd1, and Sqstm1 (p62) or the catalytic/modify subunit of glutamate-cysteine ligase (Gclc/Gclm). Autophagy formation and APAP-cysteine adduct (APAP-CYS) clearance were decreased in Egr1 KO mice administered with APAP. The EGR1 deletion reduced hepatic cyclin D1 expression at 6, 12, or 18 h post APAP administration. Meanwhile, the EGR1 deletion also decreased hepatic p62, Gclc and Gclm expression, GCL enzymatic activity, and glutathione (GSH) content and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) activation and thus aggravated oxidative liver injury induced by APAP. CGA increased EGR1 nuclear accumulation; enhanced hepatic Ccnd1, p62, Gclc, and Gclm expression; and accelerated the liver regeneration and repair in APAP-intoxicated mice. In conclusion, EGR1 deficiency aggravated liver injury and obviously delayed liver regeneration post APAP-induced hepatotoxicity through inhibiting autophagy, enhancing liver oxidative injury, and retarding cell cycle progression, but CGA promoted the liver regeneration and repair in APAP-intoxicated mice via inducing EGR1 transcriptional activation.

Associations of Clinical Characteristics and Intestinal Flora Imbalance in Stable Chronic Obstructive Pulmonary Disease (COPD) Patients and the Construction of an Early Warning Model.

OBJECTIVE: Establish a simple predictive model and scoring rule that is suitable for clinical medical staff in respiratory departments to assess intestinal flora imbalance occurrence in stable chronic obstructive pulmonary disease (COPD) patients. METHODS: From January 1, 2019, to December 31, 2020, COPD patients (195 cases) - who attended the Outpatient Department, Respiratory and Critical Care, Yixing Hospital, Jiangsu University - were enrolled in a cross-sectional study. Based on stool examination results, patients were divided into experimental (41 cases) and control (154 cases) groups. Single-factor and logistic regression analyses were performed with the baseline data of the two groups to obtain a new predictive model, which was further simplified. RESULTS: Five predictive factors composed the model: body mass index (BMI), serum albumin (ALB), Charlson's Comorbidity Index (CCI), gastrointestinal symptom score (GSRs), and Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. The model to predict intestinal flora imbalance in stable COPD patients had an area under the ROC curve (AUC) of 0.953 [95% CI (0.924, 0.982)]. After simplifying the scoring rules, the AUC was 0.767 [95% CI (0.676, 0.858)]. CONCLUSION: In the current study, we obtained a model that could effectively predict intestinal flora imbalance risk in stable COPD patients, being suitable for implementation in early treatments to improve the prognosis. Moreover, all indicators can be easily and simply obtained.

Study on the alleviation of Fengshi Gutong capsule on rheumatoid arthritis through integrating network pharmacology and experimental exploration.

ETHNOPHARMACOLOGICAL RELEVANCE: Fengshi Gutong (FSGT) capsule, a traditional Chinese medicine formula, has effects including warming meridians and dispersing cold, and relieving pain by dredging collaterals. FSGT is generally used for the treatment of rheumatoid arthritis (RA) in clinic in China. AIM OF THE STUDY: This study aims to investigate the alleviation provided by FSGT capsule on RA in vivo and the engaged mechanism. MATERIALS AND METHODS: The collagen-induced arthritis (CIA) mouse model was used to evaluate the alleviation of FSGT capsule on RA in vivo. Network pharmacology was used to find the potential involved molecular targets. Western-blot, Real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were conducted. Wound healing assay was performed in human umbilical vein endothelial cells (HUVECs). RESULTS: FSGT capsule (300, 900 mg/kg) alleviated RA in CIA mice with no obvious side effects. The results from network pharmacology showed that the top 6 molecular targets involved in the FSGT-provided alleviation on RA were interleukin 6 (IL-6), tumor necrosis factor α (TNFα), C-C motif chemokine 2 (CCL2), vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule-1 (ICAM-1), interleukin 1ß (IL-1ß), and these results imply the critical participation of inhibiting inflammation or angiogenesis. Next, FSGT capsule decreased the elevated serum contents of rheumatoid factor (RF) and VEGF, and some pro-inflammatory cytokines like TNFα and IL-6. Moreover, FSGT capsule also reduced the elevated protein expression of ICAM1, IL-1ß and phosphorylated protein kinase B (Akt) in synovium from CIA mice. Further in vitro results showed that totally 13 compounds from FSGT reduced the enhanced IL-1ß and inducible nitric oxide synthase (iNOS) mRNA expression in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). Meanwhile, 7 compounds from FSGT decreased the VEGF-induced HUVEC migration. Among those compounds, benzoylhypaconine (BHA), pseudoephedrine hydrochloride (PSE), glycyrrhetnic acid (GA), isoliquiritigenin (ISL), quercetin (QUER) and kaempferol (KAE) were found to inhibit both inflammation and angiogenesis in vitro. CONCLUSION: FSGT capsule ameliorates RA in CIA mice by reducing inflammation, abrogating angiogenesis and relieving pain. Some compounds in FSGT, including BHA, GA, PSE, ISL, QUER and KAE, reduced both inflammation and angiogenesis in vitro, which suggests that those compounds may contribute to the FSGT capsule-provided alleviation on RA.

Association between previously identified loci affecting telomere length and coronary heart disease (CHD) in Han Chinese population.

PURPOSE: To replicate previously confirmed telomere-length loci in a Chinese Han population with coronary heart disease (CHD), and investigate these loci and the possibility of and age at onset of CHD. PATIENTS AND METHODS: 1514 CHD patients and 2470 normal controls were recruited. Medical data including age, sex, body mass index, lipid profiles, history of hypertension, type 2 diabetes mellitus, and dyslipidemia were collected from all the participants. Seven previously identified single-nucleotide polymorphisms (SNPs) related to leucocyte telomere length were genotyped, including rs10936599 in TERC, rs2736100 in TERT, rs7675998 in NAF1, rs9420907 in OBFC1, rs8105767 in ZNF208, rs755017 in RTEL1, and rs11125529 in ACYP2. RESULTS: No significant difference in genotype frequencies from the Hardy-Weinberg equilibrium test was noted for all tested SNPs both in the CHD patients and the normal controls. No polymorphism was observed for rs9420907, and AA genotype was noted in both the CHD patients and the controls. Neither the genotype nor the allele frequencies of rs2736100, rs8105767, rs11125529, and rs2967374 were significantly different between the CHD patients and the normal controls. For rs10936599 and rs755017, statistical difference was found for the allele frequency but not genotype. Distributions of genotype and allele were significantly different between the two groups for rs7675998. The odds ratio for carriers of CHD was 2.127 (95% confidence interval: 1.909-2.370) for the A allele of rs7675998. By one-way analysis of variance test, rs7675998 was associated with the onset age of CHD. CHD patients with the AA genotype of rs7675998 had significantly lower onset age (P<0.05). CONCLUSION: In a Chinese Han population, NAF1 gene encoding proteins with known function in telomere biology may influence both the possibility of and the age at onset of CHD, as previously reported in European studies.