Green carbon dots derived from Atractylodes macrocephala: A potential nanodrug for treating alcoholic gastric ulcer.

Alcoholic gastric ulcer is a common acute gastric injury disease. The drugs currently used in clinical practice not only cannot fundamentally treat gastric injury, but also have serious side effects. There is an urgent demand for the discovery of a mild drug to treat alcoholic gastric ulcers. Herein, the green carbon dots derived from charred Atractylodes macrocephala (CAM-CDs) were acquired and have been proven to be safe and effective in alleviating alcoholic gastric ulcers at an inhibition rate up to 60%. CAM-CDs can markedly attenuate the gastric mucosa damage such as mucosal defect, bleeding and inflammatory cell infiltration by histopathological examination. Serum and tissue inflammatory cytokine measurements, as well as immunohistochemistry results, indicate that its mechanism of gastric mucosal protection may involve the reduction of IL-1ß and TNF-α by regulating inflammatory signaling pathway of the NF-κB/NLRP3 axis, as well as elevation of IL-10 levels. CAM-CDs also can reduce oxidative stress markers (MDA), increase PGE2 and mucin secretion (MUC5AC), and it simultaneously exerts slight inhibition of hydrogen potassium ATPase and pepsin activity to protect gastric mucosa, as well as increases the microbial diversity and regulates species composition of gut microbiota in rats with gastric ulcer. Our work provides a new perspective on utilizing carbon-based nanomaterials in the development of new mild drugs.

An Integrative Pharmacology-Based Analysis of Refined Qingkailing Injection Against Cerebral Ischemic Stroke: A Novel Combination of Baicalin, Geniposide, Cholic Acid, and Hyodeoxycholic Acid.

Stroke is the second leading cause of death after heart disease globally and cerebral ischemic stroke accounts for approximately 70% of all incident stroke cases. We selected four main compounds from a patent Chinese medicine, Qingkailing (QKL) injection, including baicalin from Scutellaria baicalensis Georgi (Huang Qin), geniposide from Gardenia jasminoides J. Ellis (Zhizi), and cholic acid and hyodeoxycholic acid from Bovis Calculus (Niuhuang) with a ratio of 4.4:0.4:3:2.6 m/m, to develop a more efficacious and safer modern Chinese medicine injection against ischemic stroke, refined QKL (RQKL). In this study, we investigated multiple targets, levels, and pathways of RQKL by using an integrative pharm\acology combining experimental validation approach. In silica study showed that RQKL may regulate PI3K-Akt, estrogen, neurotrophin, HIF-1, MAPK, Hippo, FoxO, TGF-beta, NOD-like receptor, apoptosis, NF-kappa B, Wnt, chemokine, TNF, Toll-like receptor signaling pathways against ischemic stroke. The experimental results showed that RQKL improved neurological function and prevented infract volume and blood-brain-barrier damage. RQKL inhibited microgliosis and astrogliosis, and protected neurons from ischemic/reperfusion injury. RQKL also inhibited cell apoptosis and affecting the ratio of the anti-apoptosis protein B-cell lymphoma-2 (Bcl2) and pro-apoptosis protein Bcl2-associated X protein (Bax). Western blot analysis showed that RQKL activated AKT/PI3K signaling pathway and antibody array showed RQKL inhibited inflammatory response and decreased proinflammatory factor Tnf, Il6, and Il1b, and chemokines Ccl2, Cxcl2, and Cxcl3, and increased anti-inflammatory cytokine Il10. In conclusion, RQKL protected tissue against ischemic stroke through multiple-target, multiple signals, and modulating multiple cell-types in brain. This study not only promoted our understanding of the role of RQKL against ischemic stroke, but also provided a pattern for the study of Chinese medicine combining pharmaceutical Informatics and system biology methods.

Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway.

BACKGROUND: Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation. METHODS: We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210-230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively. RESULTS: Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1ß, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation. CONCLUSIONS: QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.

A Systems Pharmacology-Based Study of the Molecular Mechanisms of San Cao Decoction for Treating Hypertension.

Traditional Chinese medicine (TCM) has a longstanding history and has gained widespread clinical applications. San Cao Decoction (SCD) is an experience prescription first formulated by Prof. Duzhou Liu. We previously demonstrated its antihypertensive effects; however, to systematically explain the underlying mechanisms of action, we employed a systems pharmacology approach for pharmacokinetic screening and target prediction by constructing protein-protein interaction networks of hypertension-related and putative SCD-related targets, and Database for Annotation, Visualization, and Integrated Discovery enrichment analysis. We identified 123 active compounds in SCD and 116 hypertension-related targets. Furthermore, the enrichment analysis of the drug-target network showed that SCD acts in a multidimensional manner to regulate PI3K-Akt-endothelial nitric oxide synthase signaling to maintain blood pressure. Our results highlighted the molecular mechanisms of antihypertensive actions of medicinal herbs at a systematic level.

Geniposide protects against hypoxia/reperfusion-induced blood-brain barrier impairment by increasing tight junction protein expression and decreasing inflammation, oxidative stress, and apoptosis in an in vitro system.

The blood-brain barrier (BBB) is involved in the pathogeneses of ischemic stroke (IS). Geniposide (GEN), an iridoid glycoside isolated from Gardenia jasminoides Ellis, has been used for the treatment of IS. However, the effects of GEN on the BBB are poorly understood. In vitro disease models of the BBB could be very helpful for the elucidation of underlying mechanisms and the development of novel therapeutic strategies. Therefore, we established an in vitro BBB model composed of primary cultures of brain microvascular endothelial cells and astrocytes. We then used this in vitro model to investigate the effect of GEN on the function of the BBB. Oxygen glucose deprivation and reoxygenation (OGD/R) significantly increased permeability and cell apoptosis in this in vitro BBB model. Notably, GEN pretreatment effectively improved the BBB function by decreasing the permeability of the BBB, promoting expression of tight junction proteins (zonula occludens-1, claudin-5, and occludin) and gamma-glutamyl transpeptidase, increasing transendothelial electrical resistance, mitigating oxidative stress damage and the release of inflammatory cytokines, downregulating the expression levels of matrix metallopeptidases-9 (MMP-9) and MMP-2, and increasing the release of brain derived neurotrophic factor and glial cell derived neurotrophic factor. Therefore, GEN can ameliorate the BBB dysfunction induced by OGD/R conditions through multiple protective mechanisms. The findings suggest that GEN may be an appropriate drug for restoring the barrier function of the BBB.

Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma.

Liver cancer is the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) accounts for the greatest proportion of these deaths. Baicalein, a flavonoid isolated from the root of Scutellariae radix, is considered a potential candidate to treat HCC. However, the underlying molecular mechanisms remain poorly understood. In the present study, a network pharmacological approach was combined with microarray data (GSE95504) acquired from the Gene Expression Omnibus database to reveal the therapeutic mechanisms of action of baicalein at a systemic level. We identified 38 baicalein targets and 76 differently expressed genes (DEGs) following treatment with baicalein, including 55 upregulated and 21 downregulated genes. The DEGs were significantly enriched in the biological functions of apoptosis, endoplasmic reticulum stress, and PERK-mediated unfolded protein response. Protein-protein interaction (PPI) network construction and topological screening revealed a core module of PPIs including two baicalein targets, TP53 and CDK1, and two downregulated DEGs, HSPA1A and HSPA1B. Expression and survival data for these genes in the module derived from Gene Expression Profiling Interactive Analysis (GEPIA) were subjected to Kaplan-Meier analysis of overall survival and disease-free survival. Overexpression of CDK1, BRCA1, TUBB, HSPA1A, HSPA1B, and HSPA4 was associated with significantly worse overall survival, while overexpression of CDK1, CLU7, BRCA1, and TUBB was associated with significantly worse disease-free survival. These data suggest that baicalein exerts therapeutic effects against HCC via a PPI network involving TP53, CDK1, HSPA1A, and HSPA1B.

Top 100 cited articles on rheumatoid arthritis: A bibliometric analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a worldwide health issue; although the prospects for most patients are favorable, many still do not respond to the current therapies. Numerous articles related to RA have been published in the past 3 decades; an analysis of the most cited articles in this field was undertaken to identify important articles regarding RA related to pathogenesis, diagnosis, and treatment. METHODS: We searched the Web of Science and collected the general information of the top 100 cited articles. The citation number, publication year, authorship, impact factor (IF) of the journal in the publication year, country origins, article types, and funding source were evaluated. RESULTS: The total citations of the top 100 articles varied from 11,922 to 556 and were published between 1985 and 2014. These articles were published in 24 journals, led by Arthritis and Rheumatism (n = 33), followed by the New England Journal of Medicine (n = 15). Most of the articles (n = 80) were produced by ≥5 authors. They were from 34 countries, and the United Stated contributed to most of the articles (n = 58), followed by the United Kingdom (n = 42). The article types were divided into clinical study (n = 55), review (n = 17), meta-analysis (n = 4), clinical guideline (n = 10), and basic science (n = 14). Eighty-seven percent of the articles were supported either by public organizations or medical companies. CONCLUSION: This study provided insights into the development of publications and their citations of RA in the past 3 decades. Clinical studies or clinical guidelines published in high-impact journals were more likely to be cited in the field of RA. The latest publications may not be included in the top 100 cited articles, as the more recent studies have not had sufficient time to accumulate the number of citations.

Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review).

Ischemic stroke is one of the main causes of death and disablement globally. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is established as a sensor of detecting cellular damage and modulating inflammatory responses to injury during the progress of ischemic stroke. Inhibiting or blocking the NLRP3 inflammasome at different stages, including expression, assembly, and secretion, may have great promise to improve the neurological deficits during ischemic stroke. The current review provides a comprehensive summary of the current understanding in the literature of the molecular structure, expression, and assembly of the NLRP3 inflammasome, and highlights its potential as a novel therapeutic target for ischemic stroke.

Synergistic neuroprotective effects of Geniposide and ursodeoxycholic acid in hypoxia-reoxygenation injury in SH-SY5Y cells.

Endoplasmic reticulum stress (ERS) and autophagy activation play important roles in the process of cerebral ischemia/reperfusion (I/R) injury. The synergistic protective effects of Geniposide and ursodeoxycholic acid against cellular apoptosis caused by oxygen-glucose deprivation-reoxygenation (OGD/R) were investigated using a Cell Counting Kit-8 assay, lactate dehydrogenase (LDH) assay, flow cytometry, quantitative polymerase chain reaction (qPCR), and western blotting to examine cellular viability, apoptosis, reactive oxygen species (ROS) levels, mRNA and protein levels, respectively, in relation to ERS and autophagy. We found that pretreatment with Geniposide improved cellular viability. Moreover, treatment with a combination of Geniposide and Tauroursodeoxycholic acid (TUDCA) (GT) protected injured cells better than Geniposide alone. Further studies showed that the increase in cellular ROS levels, and the overexpression of mRNA and proteins related to OGD/R-induced ERS and autophagy, were both counteracted by GT. Our study indicates that the protective effects of GT on OGD/R-induced apoptosis in SH-SY5Y cells are associated with the inhibition of ERS and autophagy.

Effect of traditional Chinese medicine formula Sinisan on chronic restraint stress-induced nonalcoholic fatty liver disease: a rat study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease worldwide, and it is always regarded as a consequence of a sedentary, food-abundant lifestyle, sitting for an extended time, and a low physical activity level, which often coincide with chronic and long-lasting psychological stress. A Chinese medicine Sinisan (SNS) may be a potential formula for treating this kind of disease. METHODS: In this study, a long-term chronic restraint stress protocol was used to investigate the mechanism underlying stress-induced NALFD. To investigate the effect of SNS treatment on stress-induced NAFLD, we measured the liver and serum values of total cholesterol (TC), triglyceride (TG), liver free fatty acids (FFA), low-density lipoprotein, superoxide dismutase, tumor necrosis factor-α, malondialdehyde, interleukin (IL)-6, and serum values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Results are shown as a mean ± standard deviation. Significant differences between the groups were evaluated using the Student t-test. For multiple comparisons, one-way analysis of variance (ANOVA) was used. If the results of ANOVA indicated significant differences, post hoc analysis was performed with the Tukey test or Dunnett test, and p < 0.05 was considered statistically significant. RESULTS: Long-term chronic stress led to steatosis and non-alcoholic steatohepatitis. Additionally, SNS treatment significantly increased body weight gain (p < 0.01) and sucrose preference (p < 0.001), and it reduced the liver values of TC, TG, and FFA (p < 0.05). SNS also reduced the serum values of AST and ALT (p < 0.001), and the liver value of IL-6 (p < 0.01). CONCLUSIONS: This study's results demonstrate that psychological stress may be a significant risk factor of NAFLD. Furthermore, the traditional Chinese medicine formula SNS may have some beneficial effect in antagonizing psychological stress and stress-related NAFLD.

Erythropoietin Pathway: A Potential Target for the Treatment of Depression.

During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment.