Integrative approach using network pharmacology, bioinformatics, and experimental methods to explore the mechanism of cantharidin in treating colorectal cancer.

Cantharidin, a terpenoid produced by blister beetles, has been used in traditional Chinese medicine to treat various ailments and cancers. However, its biological activity, impact, and anticancer mechanisms remain unclear. The Cantharidin chemical gene connections were identified using various databases. The GSE21815 dataset was used to collect the gene expression information. Differential gene analysis and gene ontology analyses were performed. Gene set enrichment analysis was used to assess the activation of disease pathways. Weighted gene co-expression network analysis and differential analysis were used to identify illness-associated genes, examine differential genes, and discover therapeutic targets via protein-protein interactions. MCODE analysis of major subgroup networks was used to identify critical genes influenced by Cantharidin, examine variations in the expression of key clustered genes in colorectal cancer vs. control samples, and describe the subject operators. Single-cell GSE188711 dataset was preprocessed to investigate Cantharidin's therapeutic targets and signaling pathways in colorectal cancer. Single-cell RNA sequencing was utilized to identify 22 cell clusters and marker genes for two different cell types in each cluster. The effects of different Cantharidin concentrations on colorectal cancer cells were studied in vitro. One hundred and ninety-seven Cantharidin-associated target genes and 480 critical genes implicated in the development of the illness were identified. Cantharidin significantly inhibited the proliferation and migration of HCT116 cells and promoted apoptosis at certain concentrations. Patients on current therapy develop inherent and acquired resistance. Our study suggests that Cantharidin may play an anti-CRC role by modulating immune function.

CircPACRGL promoted cell proliferation, migration and invasion as well as inhibited cell apoptosis in colorectal cancer via regulation of the miR-330-3p/CNBP axis.

CircRNAs are a member of noncoding RNAs and have been verified to play an important regulatory role in cancers. In CRC, the regulatory mechanisms of various circRNAs have not been elucidated. The expression of circPACRGL and miR-330-3p was detected with qRT-PCR. The protein expression of CDK4, MMP-9, Bcl-2, Bax, cellular nucleic acid-binding protein (CNBP) and ß-actin was measured with western blot. Cell proliferation was analyzed using MTT assay, colony formation assay, and EDU assay. Cell apoptosis was detected using flow cytometry. Cell migration and invasion were measured with wound healing and transwell invasion assay. Luciferase reporter assay and RIP assay was used to determine the relationship of among miR-330-3p, circPACRGL and CNBP in CRC cells. In this study, we found that circPACRGL and CNBP expressed high and miR-330-3p expressed low in CRC tissues and cells. Functional experiments showed that inhibition of circPACRGL reduced cell proliferation, migration and invasion in CRC. In addition, knockdown of circPACRGL contributed to cell apoptosis in CRC. Dual-luciferase report assay determined that circPACRGL was a miR-330-3p sponge molecular and CNBP was a target of miR-330-3p. Reversed experiments showed that the effects of sh-circPACRGL transfection on CRC cells were rescued by up-regulating CNBP expression. In this study, we for the first time found a novel regulatory network of circPACRGL in CRC. The results manifested that circPACRGL affected tumor growth by targeting miR-330-3p/CNBP axis in CRC, highlighting the potential of circPACRGL as a therapeutic target for colorectal cancer.

Dexmedetomidine suppresses the isoflurane-induced neurological damage by upregulating Heme Oxygenase-1 via activation of the mitogen-activated protein kinase kinase 1/extracellular regulated protein kinases 1/nuclear factor erythroid 2-related factor 2 axis in aged rats.

Dexmedetomidine (DEX) displays a neuroprotective role in aged rats with isoflurane (ISO)-induced cognitive impairment through antioxidant, and anti-inflammatory, and anti-apoptotic effects. Therefore, the present study was performed to define the molecular mechanism of DEX on ISO-induced neurological impairment in aged rats in relation to the MEK1/ERK1/Nrf2/HO-1 axis. The study enrolled elderly patients undergoing ISO anesthesia. Patient cognitive function following treatment with DEX was evaluated using mini-mental state examination (MMSE). The results revealed that DEX supplementation of anesthesia contributed to higher MMSE scores in patients one week post treatment. Rat model of neurological impairment was also induced in 18-month-age Wistar rats by ISO, followed by DEX treatment. Based on the results of Morris water maze experiment, ELISA, and TUNEL and hematoxylin-eosin staining, in vivo experiments confirmed that DEX could reduce the oxidative stress and neurological damage induced by ISO in rats. DEX activated the nuclear factor erythroid 2-related factor (Nrf2)/Heme Oxygenase 1 (HO-1) pathway. DEX upregulated the expression of Nrf2 and HO-1 by activating the MEK1/ERK1 pathway, whereby attenuating the ISO-caused oxidative stress and neurological damage in rats. Collectively, DEX suppresses the ISO-induced neurological impairment in the aged rats by promoting HO-1 through activation of the MEK1/ERK1/Nrf2 axis.

Polygonatum sibiricum polysaccharides prevent LPS-induced acute lung injury by inhibiting inflammation via the TLR4/Myd88/NF-κB pathway.

Inflammation plays an important role in cases of acute lung injury (ALI), and the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway, which can be regulated by Polygonatum sibiricum polysaccharides (PSPs), is closely related to the dynamics of lipopolysaccharide (LPS)-induced inflammation. Thus, we sought to evaluate whether or not PSPs prevent LPS-induced ALI by way of inhibiting inflammation via the TLR4/NF-κB pathway in rats. We established an ALI rat model by tracheal instillation of LPS, and by pre-injection of PSPs into rats to examine PSPs in the ALI rat model. We found that PSPs attenuated LPS-induced lung pathological changes in ALI rats, decreased LPS-induced myeloperoxidase (MOP) activity, and elevated malondialdehyde (MDA) levels in lung tissue. However, PSPs also decreased the LPS-induced increase in the neutrophil ratio, and decreased inflammatory factor levels in bronchoalveolar lavage fluid (BALF). Moreover, PSPs decreased LPS-induced increases in inflammatory factors measured by mRNA expression, and altered the levels of expression of TLR4, medullary differentiation protein 88 (Myd88), p-IKB-α/IKB-α and p-p65/p65 proteins in lung tissue. In vitro, PSPs also reduced apoptosis induced by LPS in BEAS-2B cells by suppressing inflammation through its effect of inhibiting the TLR4/NF-κB pathway. In conclusion, our results suggest that PSPs may be a potential drug for effective treatment of LPS-induced ALI, due to the ability to inhibit inflammation through effects exerted on the TLR4/Myd88/NF-κB pathway.

Selection of Patients' Recumbent Position Laterality According to Physician Handedness Bias Increases the Success Rate of Lumbar Puncture: A Multicenter Study.

BACKGROUND: Lumbar puncture (LP) is a medical procedure required during spinal anesthesia and for obtaining cerebrospinal fluid samples in the diagnosis of neurological disorders. The aim of this study was to assess the effects of physicians' handedness bias and the laterality of patients' recumbent position on the success rate of LPs. METHODS AND PATIENTS: A prospective multicenter study including 36 physicians (18 left-handed and 18 right-handed) and 7200 patients was conducted in 6 medical centers. In each center, 1200 patients were randomized into group L (LPs performed by left-handed physicians) or group R (LPs performed by right-handed physicians). Each physician performed 200 cases of LPs, of which the laterality of the recumbent position (either on the left or right side) was decided after a second randomization. A successful LP was considered when the free flow of cerebrospinal fluid was observed upon the first attempt. RESULTS: There was no significant difference in patient characteristics between groups L and R. Right-handed physicians had a significantly higher LP success rate with patients in the left lateral recumbent position (LRP) (1595/1800 vs. 1408/1800; odds ratio, 0.539; 95% confidence interval, 0.348-0.836; P=0.006). For left-handed physicians, the LP success rate was higher when patients were in the right LRP (1424/1800 vs. 1593/1800, odds ratio, 0.449; 95% confidence interval, 0.283-0.711; P=0.001). Patients' age, sex, height, and weight were not statistically related to LP success during multivariate analyses. CONCLUSIONS: Physicians handedness bias and patient laterality of recumbent position affects the success of LPs. Right-handed physicians have a greater chance of performing successful LPs when patients are in the left LRP, and vice versa.

Comprehensive preoperative regime of selective gut decontamination in combination with probiotics, and smectite for reducing endotoxemia and cytokine activation during cardiopulmonary bypass: A pilot randomized, controlled trial.

BACKGROUND: Both selective digestive decontamination (SDD) and probiotics have been reported to reduce endotoxemia. However, the available results are conflicting and few studies have investigated the combined effect of SDD and probiotics. This study aimed to examine the effectiveness of a comprehensive preoperative regimen of SDD in combination with probiotics and smectite on perioperative endotoxemia and cytokine activation in patients who underwent elective cardiac surgery with cardiopulmonary bypass (CPB) in a pilot, prospective, randomized, controlled trial. METHODS: Patients who underwent elective Aortic Valve Replacement or Mitral Valve Replacement surgery from July 2010 to March 2015 were included. In total, 30 eligible patients were randomly assigned to receive either the comprehensive preoperative regimen (n = 15) (a combination of preoperative SDD, probiotics, and smectite) or the control group (n = 15) who did not receive this treatment. The levels of endotoxin, IL-6, and procalcitonin were measured at the time before anesthesia induction, immediately after cardiopulmonary bypass (CPB), 24 hours after CPB, and 48 hours after CPB. The primary outcomes were changes in endotoxin, IL-6, and procalcitonin concentrations after CPB. RESULTS: The mean levels of change in endotoxin levels after CPB in patients receiving the comprehensive preoperative regimen was marginally significantly lower than those in control group (F = 4.0, P = .0552) but was not significantly different for procalcitonin (F = .14, P = .7134). An interaction between group and time for IL-6 was identified (F = 4.35, P = .0231). The increase in IL-6 concentration immediately after CPB in the comprehensive preoperative group was significantly lower than that in the control group (P = .0112). The changes in IL-6 concentration at 24 hours and 48 hours after CPB were not significant between the comprehensive preoperative group and control group. CONCLUSION: The present pilot, prospective, randomized, controlled study in patients undergoing cardiac surgery with CPB demonstrated that 3 days of a comprehensive preoperative regime of SDD in combination with probiotics and smectite may reduce the endotoxin and IL-6 levels after CPB compared with the control group.

Astragalus polysaccharides combined with ibuprofen exhibit a therapeutic effect on septic rats via an anti-inflammatory cholinergic pathway.

The aim of the present study was to investigate the effects of Astragalus polysaccharides (APS) in combination with ibuprofen (IBU) in the treatment of sepsis and the underlying mechanism. The combined drug treatment was evaluated in a rat model of cecal ligation and puncture (CLP). The serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and acetylcholine (ACh) were determined. Nicotinic acetylcholine (nAChR) α7 receptor expression and histopathological changes in the lung tissue were also observed. When compared with untreated rats and rats treated with either component alone, the combined treatment significantly decreased the production of TNF-α and IL-6 (P<0.05), and increased nAChR α7 receptor mRNA expression and the release of ACh in the serum (P<0.05). These results demonstrated that APS combined with IBU can effectively reduce the generation of inflammatory mediators in the serum of CLP-induced septic rats. These effects may be mediated via a cholinergic anti-inflammatory pathway involving nAChR α7.

Effect of intercostal nerve block combined with general anesthesia on the stress response in patients undergoing minimally invasive mitral valve surgery.

The aim of the present study was to investigate the effect of intercostal nerve block combined with general anesthesia on the stress response and postoperative recovery in patients undergoing minimally invasive mitral valve surgery (MIMVS). A total of 30 patients scheduled for MIMVS were randomly divided into two groups (n=15 each): Group A, which received intercostal nerve block combined with general anesthesia and group B, which received general anesthesia alone. Intercostal nerve block in group A was performed with 0.5% ropivacaine from T3 to T7 prior to anesthesia induction. In each group, general anesthesia was induced using midazolam, sufentanil, propofol and vecuronium. Central venous blood samples were collected to determine the concentrations of cortisol, glucose, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) at the following time points: During central venous catheterization (T1), 5 min prior to cardiopulmonary bypass (T2), perioperative (T3) and 24 h following surgery (T4). Clinical data, including parameters of opioid (sufentanil) consumption, time of mechanical ventilation, duration of intensive care unit (ICU) stay, visual analog scale scores and any complications arising from intercostal nerve block, were recorded. Levels of cortisol, glucose, IL-6 and TNF-α in group A were significantly lower than those in group B at T2 (all P<0.001; cortisol, P<0.05), T3 (all P<0.001) and T4 (all P<0.001; glucose, P<0.05), suggesting that intercostal nerve block combined with general anesthesia may inhibit the stress response to MIMVS. Additionally, intercostal nerve block combined with general anesthesia may significantly reduce sufentanil consumption (P<0.001), promote early tracheal extubation (P<0.001), shorten the duration of ICU stay (P<0.01) and attenuate postoperative pain (P<0.001), compared with general anesthesia alone. Thus, these results suggest that intercostal nerve block combined with general anesthesia conforms to the concept of rapid rehabilitation surgery and may be suitable for clinical practice.

Effect of dexmedetomidine priming on convulsion reaction induced by lidocaine.

To study the effect of dexmedetomidine priming on convulsion reaction induced by lidocaine.The New Zealand white rabbits were applied for the mechanism study of dexmedetomidine priming for preventing convulsion reaction induced by lidocaine. The influence of dexmedetomidine priming with different doses on the time for convulsion occurrence and the duration time of convulsion induced by lidocaine, as well as contents of excitatory amino acids (aspartate [Asp], glutamate [Glu]) and inhibitory amino acids (glycine [Gly], γ-aminobutyric acid [GABA]) in the brain tissue were investigated.With 3 and 5 µg/kg dexmedetomidine priming, the occurrence times of convulsion were prolonged from 196 seconds to 349 and 414 seconds, respectively. With dexmedetomidine priming, the contents of excitatory amino acids (Asp, Glu) were much reduced at occurrence time of convulsion comparing with that without dexmedetomidine priming, while content of inhibitory amino acids Gly was much enhanced.The application of dexmedetomidine before local anesthetics can improve intoxication dose threshold of the lidocaine, delay occurrence of the convulsion, and helped for the recovery of convulsion induced by lidocaine. The positive effect of dexmedetomidine on preventing convulsion would owe to not only the inhibition of excitatory amino acids (Asp, Glu), but also the promotion of inhibitory amino acids Gly secretion.