The enhanced therapeutic effects and mechanisms of certain herbal combination in various herbal prescriptions are mostly unclear. A combination of two herbs, namely Ephedrae herba (EH) and Coicis ...semen (CS), has been commonly prescribed for obesity. In our previous work, the combination of EH and CS was studied using network pharmacological approach to predict its pharmacological targets and in vitro experiments to evaluate its efficacy on obesity. Although we demonstrated enhanced anti-adiposity effects of the combination on matured adipocytes, the molecular mechanisms and contributing compounds underlying the effects of EH-CS combination on adiposity or adipogenesis were not fully elucidated. The current study adopted integrated bioinformatics analysis to precisely validate potential targets of EH-CS by screening differentially expressed genes (DEGs) of morbid obesity patients from NCBI gene expression omnibus (GEO). Based on the functional cluster analysis of down-regulated DEGs, the anti-adipogenesis mechanism of EH-CS combination was speculated with KEGG enrichment analysis. Furthermore, we investigated the combinational effects of EH and coixol, or stigmasterol, the two compounds in CS which were expected to have main beneficial effects in metabolic diseases. Moreover, distinct effect of the combination on transcriptional activity of glucocorticoid receptor (GR) was investigated using electrophoretic mobility shift assay (EMSA). The EH-CS combination was predicted to modulate down-regulated genes which are involved in KEGG pathways crucial to metabolic disease in morbidly obese individuals. The combination of EH with CS compounds significantly increased the phosphorylation of acetyl-coA carboxylase (ACC), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) in 3T3-L1 cells and decreased intracellular lipid accumulation. The two CS compounds significantly increased the anti-adipogenesis/lipogenesis effects of EH by inhibiting the gene expression levels. Finally, the combination of EH and coixol inhibited dexamethasone-induced GR translocation to the nucleus and transcriptional binding activity in adipocytes. The combination of EH and CS could be considered a therapeutic strategy for treating metabolic diseases, including obesity.
Targeting Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD2) signaling is regarded as a potential strategy for treating inflammatory diseases. Saponaria officinalis L. is rich in ...saponin, which include quillaic acid, gypsogenin, saponarin, and hederagenin. We evaluated the pharmacological activity of a Saponaria officinalis extract in THP‐1 derived macrophages and RAW264.7 macrophages. TLR4/MyD88 complex formation and downstream signals were investigated by co‐immunoprecipitation (Co‐IP). In silico docking simulation was conducted to predict binding scores and perform 3D modeling of saponarin‐TLR4/MD2 complex. A hexane fraction of Saponaria officinalis (SH) and fr.1 (a sub‐fraction 1 of SH) inhibited mitogen‐activated protein kinase (MAPK) signaling, nuclear factor kappa b (NF‐κB) activity, cytokine production, and the expressions of marker genes specific for M1 polarization. The inhibitory effects of fr.1 and saponarin on TLR4/MyD88 complex formation were observed by western blotting TLR4 co‐immunoprecipitated proteins. Saponarin and fr.1 markedly attenuated LPS‐induced inflammatory cytokines, thus reducing mortality and morphological abnormality in zebrafish larvae. Finally, docking simulation revealed that saponarin can directly interact with TLR4/MD2 complex to inhibit downstream signalings. Our findings suggest that saponarin reduces downstream inflammatory response by disrupting TLR4/MD2 complex and blocking MyD88‐dependent inflammatory signaling.
Herbal combinations are regarded as basic strategy in oriental medicine with various purposes. Ephedrae herba (EH) and Coicis semen (CS) are two herbal medicines used to treat obesity in many herbal ...prescriptions, yet the effect and significance of this herbal pair have not been evaluated.
This study is to elucidate the effect of a novel herbal pair, EH-CS, on obesity and identify the key synergistic mechanism underlying it.
We investigated the network of herbs comprising the anti-obesity herbal prescriptions. Using the tools of network pharmacology, we investigated the compound-target interactions of EH and CS in combination to predict their effects in combination. Five EH-CS samples with different EH to CS ratios were prepared to investigate their efficacies in adipocytes.
1-mode network analysis of herbs in prescriptions based on literature review revealed the importance of EH-CS in anti-obesity prescriptions. The herbal combination comprised of equivalent weights (1:1) of EH and CS most potently reduced mature adipocyte adiposity, although several markers of adipogenesis and lipid synthesis were more suppressed by pure EH. PTGS2 (COX-2 gene) expression, a common target of EH and CS as deduced by compound-target network analysis, was affected by EH-CS extract treatments. However, EH at high concentration (25 μg/ml) notably increased PTGS2 expression without adversely affecting cell viability. However, EH-CS combination of the same concentration markedly decreased PTGS2 gene expression.
These results show that the compounds in CS and EH act in concert to enhance the pharmacological effect of EH, but control unexpected effects of EH treatment.
Background. Physiological conduction system pacing has attracted attention to overcome the dyssynchrony problems of conventional right ventricular pacing (RVP). Left bundle branch area pacing ...(LBBAP), which complements short combing of His bundle pacing (HBP), has emerged and has proven its efficiency and safety. In addition, initial experiences of LBBAP were mainly using lumen-less pacing lead, and the feasibility of stylet-driven pacing lead (SDL) was also established. The purpose of this study is to evaluate the learning curve for LBBAP using SDL. Methods. The study enrolled 265 patients who underwent LBBAP or RVP performed by operators without previous LBBAP experience at Yonsei University Severance Hospital in Korea between December 2020 and October 2021. LBBAP was performed using SDL with an extendable helix. The learning curve was evaluated by analyzing fluoroscopy and procedure times. And, before and after reaching the learning curve, we evaluated how much the time required for the LBBAP differed from the time required for the RVP. Results. LBBAP was successful in 50 of 50 (100.0%) patients left bundle branch pacing was successful in 49 of 50 (98.0%). In 50 patients who underwent LBBAP, mean fluoroscopy and procedural times were 15.1 ± 13.5 minutes and 59.9 ± 24.8 minutes, respectively. The plateau of fluoroscopy time reached in the 25th case and the plateau of procedure time reached in the 24th case. Conclusion. During the initial experience with LBBAP, fluoroscopy and procedural times improved with increasing operator experience. For operators who were experienced in cardiac pacemaker implantation, the steepest part of the learning curve was over the first 24-25 cases. It is shorter than the previously reported learning curves of HBP.
Cardiac resynchronization therapy (CRT) strategy for heart failure with mildly reduced ejection fraction (HFmrEF) is controversial. Left bundle branch area pacing (LBBAP) is an emerging pacing ...modality and an alternative option to CRT. This analysis aimed to perform a systematic review of the literature and meta‐analysis on the impact of the LBBAP strategy in HFmrEF, with left ventricular ejection fraction (LVEF) between 35% and 50%. PubMed, Embase, and Cochrane Library were searched for full‐text articles on LBBAP from inception to July 17, 2022. The outcomes of interest were QRS duration and LVEF at baseline and follow‐up in mid‐range heart failure. Data were extracted and summarized. A random‐effect model incorporating the potential heterogeneity was used to synthesize the results. Out of 1065 articles, 8 met the inclusion criteria for 211 mid‐range heart failure patients with an implant LBBAP across the 16 centers. The average implant success rate with lumenless pacing lead use was 91.3%, and 19 complications were reported among all 211 enrolled patients. During the average follow‐up of 9.1 months, the average LVEF was 39.8% at baseline and 50.5% at follow‐up (MD: 10.90%, 95% CI: 6.56−15.23, p < .01). Average QRS duration was 152.6 ms at baseline and 119.3 ms at follow‐up (MD: −34.51 ms, 95% CI: −60.00 to −9.02, p < .01). LBBAP could significantly reduce QRS duration and improve systolic function in a patient with LVEF between 35% and 50%. Application of LBBAP as a CRT strategy for HFmrEF may be a viable option.
Average left ventricular ejection fraction (LVEF) from implant to follow‐up for baseline LVEF between 35% and 50% versus LVEF <35%.
▪ Left bundle branch area pacing (LBBAP) was found to significantly shorten QRS duration and improve systolic cardiac function in patients with a LVEF of 35%−50%.
▪ In patients with heart failure with mildly reduced ejection fraction, LBBAP resulted in a significant increase in ejection fraction.
The network pharmacology (NP) approach is a valuable novel methodology for understanding the complex pharmacological mechanisms of medicinal herbs. In addition, various in silico analysis techniques ...combined with the NP can improve the understanding of various issues used in natural product research. This study assessed the therapeutic effects of
(AT),
(PC), and
(ZO) on hyperlipidemia after network pharmacologic analysis. A protein-protein interaction (PPI) network of forty-one key targets was analyzed to discover core functional clusters of the herbal compounds. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) term enrichment analysis identified significant categories of hypolipidemic mechanisms. The STITCH database indicated a high connection with several statin drugs, deduced by the similarity in targets. AT, PC, and ZO regulated the genes related to the energy metabolism and lipogenesis in HepG2 cells loaded with free fatty acids (FFAs). Furthermore, the mixture of three herbs had a combinational effect. The herbal combination exerted superior efficacy compared to a single herb, particularly in regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1 (CPT-1). In conclusion, the network pharmacologic approach was used to assess potential targets of the herbal combination for treatment. Experimental data from FFA-induced HepG2 cells suggested that the combination of AT, PC, and ZO might attenuate hyperlipidemia and its associated hepatic steatosis.
Portulaca oleracea
L. (PO) is an edible and medicinal plant used for treating gastrointestinal diseases. However, the effects of PO on ulcerative colitis (UC) and underlying mechanisms remain ...unclear. This study investigated the effects of PO aqueous extract (POE) and PO juice (PJ) on dextran sulfate sodium (DSS)–induced UC in a mouse model and attempted to unravel their underlying mechanisms. The results revealed that PJ contains more bioactive compounds and has more overlapping targets with UC than POE. Both POE and PJ effectively reduced Disease Activity Index scores and inflammatory cell infiltration in the UC mouse model, but PJ had a better effect than POE. Furthermore, PJ inhibited pyroptosis by decreasing the expression of the NLRP3 inflammasome, while also repairing the dysfunction of the intestinal barrier by upregulating the expression of tight junction proteins. Therefore, based on the study findings, we concluded that PJ can improve DSS-induced UC and may suppress pyroptosis by interfering with the activation of the NLRP3 inflammasome.
Graphical abstract
Background: Regular exercise improves the functional ability and quality of life of patients with heart failure (HF). However, studies on the results of intensity of exercise in the older population ...are scarce, especially in the Asian population. Method and Results: A total of 8982 older people (age ≥65 years) with HF were selected from the Korean National Health Insurance Service-Senior database (2005–2012). Participants were stratified according to the levels of physical activity per week as follows: (1) inactive group; (2) insufficiently active group: 1–499 metabolic equivalent task minutes (MET-min)/week; (3) active group: 500–999 MET-min/week; and (4) highly active group: ≥1000 MET-min/week. During a median follow-up period of 3.2 years, the incidence and risk of mortality were reduced in the insufficiently active (6.7 vs. 4.2 per 100 person-years, adjusted hazard ratio HR, 0.82; 95% confidence interval CI, 0.71–0.94; p < 0.001), active (3.8 per 100 person-years; HR, 0.81; 95% CI, 0.70–0.95; p = 0.010), and highly active (2.4 per 100 person-years; HR, 0.52; 95% CI, 0.41–0.67; p < 0.001) groups compared to inactive patients. Conclusions: In older Asians with HF, increased physical activity reduced the risk of all-cause mortality. The mortality-reducing benefit started at a lower physical activity compared to the World Health Organization guideline (500–999 MET-min/week), and the risk decreased with more physical activity.
Mori fructus aqueous extracts (MFAEs) have been used as a traditional Chinese medicine for thousands of years with the function of strengthening the liver and tonifying the kidney. However, its inner ...mechanism to alleviative renal injury is unclear. To investigate the attenuation of MFAEs on nephrotoxicity and uncover its potential molecular mechanism, we established a nephrotoxicity model induced by carbon tetrachloride (CCl4). The mice were randomly divided into control group, CCl4 model group (10% CCl4), CCl4 + low and high MFAEs groups (10% CCl4 + 100 mg/kg and 200 mg/kg MFAEs). We found that MFAEs decreased the kidney index of mice, restored the pathological changes of renal structure induced by CCl4, reduced cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (Kim-1) blood urea nitrogen and creatinine contents in serum, promoted the nuclear transportation of Nrf2 (nuclear factor erythroid derived 2 like 2), elevated the expression of HO-1 (heme oxygenase 1), GPX4 (glutathione peroxidase 4), SLC7A11 (solute carrier family 7 member 11), ZO-1 (zonula occludens-1) and Occludin, suppressed the expression of Keap1 (kelch-like ECH-associated protein 1), HMGB1 (High Mobility Group Protein 1), ACSL4 (acyl-CoA synthetase long chain family member 4) and TXNIP (thioredoxin interacting protein), upregulated the flora of Akkermansia, Anaerotruncus, Clostridium_sensu_stricto, Ihubacter, Alcaligenes, Dysosmobacter, and downregulated the flora of Clostridium_XlVa, Helicobacter, Paramuribaculum. Overlapped with Disbiome database, Clostridium_XlVa, Akkermansia and Anaerotruncus may be the potential genera treated with renal injury. It indicated that MFAEs could ameliorate kidney injury caused by CCl4 via Nrf2 signaling.
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•Mori Fructus aqueous extracts (MFAEs) relieved chronic renal injury through ferroptosis, fibrosis and intestinal flora.•Nrf2 signaling was activated by MFAEs to decrease ferroptosis in renal.•MFAEs regulated the abundance of intestinal flora and affected the progression of renal injury.
Pingwei San (PWS) has been used for more than a thousand years as a traditional Chinese medicine prescription for treating spleen-deficiency diarrhea (SDD). Nevertheless, the exact mechanism by which ...it exerts its antidiarrheal effects remains unclear. The objective of this investigation was to explore the antidiarrheal efficacy of PWS and its mechanism of action in SDD induced by Rhubarb. To this end, UHPLC-MS/MS was used to identify the chemical composition of PWS, while the body weight, fecal moisture content, and colon pathological alterations were used to evaluate the effects of PWS on the Rhubarb-induced rat model of SDD. Additionally, quantitative polymerase chain reaction (qPCR) and immunohistochemistry were employed to assess the expression of inflammatory factors, aquaporins (AQPs), and tight junction markers in the colon tissues. Furthermore, 16S rRNA was utilized to determine the impact of PWS on the intestinal flora of SDD rats. The findings revealed that PWS increased body weight, reduced fecal water content, and decreased inflammatory cell infiltration in the colon. It also promoted the expression of AQPs and tight junction markers and prevented the loss of colonic cup cells in SDD rats. In addition, PWS significantly increased the abundance of
,
, and
, while decreasing the abundance of
and
in the feces of SDD rats. The LEfSe analysis revealed that
,
, and
were relatively enriched in the PWS group. Overall, the findings of this study indicate that PWS exerted a therapeutic effect on Rhubarb-induced SDD in rats by both protecting the intestinal barrier and modulating the imbalanced intestinal microbiota.
