Potential of semen coicis in enhancing the anti-tumor effects of PD-1 inhibitor on A549 cell lines by blocking the PI3K-AKT-mTOR pathway.

BACKGROUND: The objective of this research was to investigate how the combination of semen coicis extract and PD-1 inhibitors can potentially work together to enhance the anti-tumor effects, with a focus on understanding the underlying mechanism. METHODS: We obtained the active components and specific targets of semen coicis in the treatment of NSCLC from various databases, namely TCMSP, GeneCard, and OMIM. By utilizing the STRING database and Cytoscape software, we established a protein interaction network (PPI) for the active ingredient of semen coicis and the target genes related to NSCLC. To explore the potential pathways involved, we conducted gene ontology (GO) and biological pathway (KEGG) enrichment analyses, which were further supported by molecular docking technology. Additionally, we conducted cyto-inhibition experiments to verify the inhibitory effects of semen coicis alone or in combination with a PD-1 inhibitor on A549 cells, along with examining the associated pathways. Furthermore, we investigated the synergistic mechanism of these two drugs through cytokine release experiments and the PD-L1 expression study on A549 cells. RESULTS: Semen coicis contains two main active components, Omaine and (S)-4-Nonanolide. Its primary targets include PIK3R1, PIK3CD, PIK3CA, AKT2, and mTOR. Molecular docking experiments confirmed that these ingredients and targets form stable bonds. In vitro experiments showed that semen coicis demonstrates inhibitory effects against A549 cells, and this effect was further enhanced when combined with PD-1 inhibitors. PCR and WB analysis confirmed that the inhibition of the PI3K-AKT-mTOR pathway may contribute to this effect. Additionally, semen coicis was observed to decrease the levels of IFN-γ, IL-6, and TNF-α, promoting the recovery of the human anti-tumor immune response. And semen coicis could inhibit the induced expression of PD­L1 of A549 cells stimulated by IFN­Î³ as well. CONCLUSION: Semen coicis not only has the ability to kill tumor cells directly but also alleviates the immunosuppression found in the tumor microenvironment. Additionally, it collaboratively enhances the effectiveness of PD-1 inhibitors against tumors by blocking the activation of PI3K-AKT-mTOR.

Effect of the combination of he-sea and front-mu points on enteral nutrition feeding intolerance in critical illness patients. / åˆå‹Ÿé ç©´æ²»ç–—å±é‡ç—‡æ‚£è€ è‚ å† è¥å »å–‚å »ä¸è€å—çš„ç–—æ•ˆè§‚å¯Ÿ.

OBJECTIVES: To explore the effects of the combination of he-sea and front-mu points on the feeding compliance rate, the intra-abdominal pressure, the enteral nutrition tolerance score, the score of acute physiological and chronic health evaluation (APACHE)-Ⅱ and gastrointestinal function impairment grade in the patients with enteral nutrition feeding intolerance (ENFI) of critical illness and evaluate clinical effect on ENFI after acupuncture at the he-sea and front-mu points. METHODS: Seventy patients of ENFI were randomized into a control group and an observation group, 35 cases in each one. In the control group, the patients were treated with routine regimen combined with intestinal nutrition support. In the observation group, on the basis of the treatment as the control group, acupuncture was applied to Shangwan (CV13), Zhongwan (CV12), Xiawan (CV10), Qihai (CV6) and Guanyuan (CV4), as well as bila-teral Neiguan (PC6), Zusanli (ST36), Xiajuxu (ST39), Shangjuxu (ST37), Tianshu (ST25) and Daheng (SP15). Of those acupoints, ST25 and SP15 on the same side were attached to one pair of electrodes (20 Hz/100 Hz). Acupuncture was delivered once daily, 30 min each time and for consecutive 7 days. During treatment, the numbers of the cases up to the feeding standard were observed everyday to calculate the feeding compliance rate. The score of enteral nutrition tolerance, the intra-abdominal pressure, the score of APACHE-Ⅱ and the level of acute gastriointestinal injury(AGI) grading were recorded. RESULTS: After treatment, the enteral feeding compliance rate was increased in comparison with that before treatment in the two groups, and the rate in the observation group was higher than that of the control group (P<0.05) except that on the 2nd day. The score of the enteral nutrition tolerance, the intra-abdominal pressure, the score of APACHE-Ⅱ and the level of AGI were all reduced (P<0.05, P<0.01) when compared with those before treatment in the two groups, and these indicators in the observation group were lower (P<0.05) than those of the control group. CONCLUSIONS: Acupuncture at the he-sea and front-mu points relieves the conditions of ENFI, improves the feeding and the recovery of gastrointestinal function, and benefits the prognosis through increasing the amount of enteral nutrition in ENFI patients.

Transcutaneous Electrical Acupoint Stimulation for Moderate to Severe Pain in Hepatocellular Carcinoma: A Protocol for a Randomized Controlled Trial.

Background: Cancer-related pain is one of the primary symptoms of patients with hepatocellular carcinoma (HCC). Previous studies have shown that transcutaneous electrical acupoint stimulation (TEAS) is effective in treating patients with acute or chronic pain. In China, it is indispensable to evaluate the efficacy of TEAS in combination with opioids for the treatment of moderate to severe HCC-related pain. Methods/Design: This is a single-center clinical, prospective randomized controlled clinical trial protocol. 104 patients will be randomly divided into the observation group and the control group in a ratio of 1:1.In addition to routine cancer pain medication, the two groups of patients will receive TEAS treatment twice a day for one week. Acupoints will include bilateral Hegu(LI4), Neiguan(PC6), Zusanli(ST36), Taichong(LR3), Ganshu(BL18), Geshu(BL17), Qimen(LR14), and Zhangmen(LR13). The treatment time is from 9:00 a.m. to 11:00 p.m. and from 4:00 p.m. to 6:00 p.m. The primary outcome measures are the Numerical Rating Scale (NRS) and the secondary outcome measures include the Brief Pain Inventory(BPI), dosage and administration duration of opioid drugs, frequency of nausea, vomiting and defecation, Karnofsky Performance Status Scale (KPS), Quality of life scale (QOL), Brief Fatigue Inventory (BFI). The outcome measures will be evaluated at baseline, during treatment and 1 week after treatment. Discussion: Results of this trial are expected to clarify the value of TEAS stimulation performed on specific points in the management of moderate to severe pain in HCC. Trial registration: Chinese clinical trial registry, ChiCTR2100044615 (http://www.chictr.org.cn), Registered on 24 March 2021.

Cytochrome P450 3A4 suppression by epimedium and active compound kaempferol leads to synergistic anti-inflammatory effect with corticosteroid.

Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to determine the effects of epimedium on CYP3A4 and whether it affects the anti-inflammatory function of CS and identify the active compound responsible for this effect. Methods: The effect of epimedium on CYP3A4 activity was evaluated using the Vivid CYP high-throughput screening kit. CYP3A4 mRNA expression was determined in human hepatocyte carcinoma (HepG2) cells with or without epimedium, dexamethasone, rifampin, and ketoconazole. TNF-α levels were determined following co-culture of epimedium with dexamethasone in a murine macrophage cell line (Raw 264.7). Active compound (s) derived from epimedium were tested on IL-8 and TNF-α production with or without corticosteroid, on CYP3A4 function and binding affinity. Results: Epimedium inhibited CYP3A4 activity in a dose-dependent manner. Dexamethasone enhanced the expression of CYP3A4 mRNA, while epimedium inhibited the expression of CYP3A4 mRNA and further suppressed dexamethasone enhancement of CYP3A4 mRNA expression in HepG2 cells (p < 0.05). Epimedium and dexamethasone synergistically suppressed TNF-α production by RAW cells (p < 0.001). Eleven epimedium compounds were screened by TCMSP. Among the compounds identified and tested only kaempferol significantly inhibited IL-8 production in a dose dependent manner without any cell cytotoxicity (p < 0.01). Kaempferol in combination with dexamethasone showed complete elimination of TNF-α production (p < 0.001). Furthermore, kaempferol showed a dose dependent inhibition of CYP3A4 activity. Computer docking analysis showed that kaempferol significantly inhibited the catalytic activity of CYP3A4 with a binding affinity of -44.73kJ/mol. Discussion: Inhibition of CYP3A4 function by epimedium and its active compound kaempferol leads to enhancement of CS anti-inflammatory effect.

Metabolic changes of different high-resolution computed tomography phenotypes of COPD after budesonide-formoterol treatment.

BACKGROUND: Metabolomics is the global unbiased analysis of all the small-molecule metabolites within a biological system. Metabolic profiling of different high-resolution computed tomography (HRCT) phenotypes of COPD patients before and after treatment may identify discriminatory metabolites that can serve as biomarkers and therapeutic agents. PATIENTS AND METHODS: 1H nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics was performed on a discovery set of plasma samples from 50 patients with stable COPD. Patients were assigned into two groups on the basis of HRCT findings including phenotype E (n=22) and phenotype M (n=28). After budesonide-formoterol treatment (160/4.5 µg ×2 inhalations twice daily for 3 months), clinical characteristics and metabolites were then compared between phenotype E pretreatment and posttreatment, phenotype M pretreatment and posttreatment, phenotype E pretreatment and phenotype M pretreatment, and phenotype E posttreatment and phenotype M posttreatment. RESULTS: Inhaled budesonide-formoterol therapy for both phenotype E (emphysema without bronchial wall thickening) and phenotype M (emphysema with bronchial wall thickening) was effective. However, phenotype E and phenotype M were different in response to therapy. Patients with phenotype M in response to therapeutic effects were significantly greater compared with phenotype E. Certain metabolites were identified, which were closely related to the treatment and phenotype. Metabolic changes in phenotype E or phenotype M after treatment may be involved with adenosine diphosphate (ADP), guanosine, choline, malonate, tyrosine, glycine, proline, l-alanine, l-valine, l-threonine leucine, uridine, pyruvic acid, acetone and metabolism disturbance. Metabolic differences between phenotype E and phenotype M in pretreatment and posttreatment covered glycine, d-glucose, pyruvic acid, succinate, lactate, proline, l-valine and leucine. CONCLUSION: Bronchial wall thickening in COPD may be an indicator for predicting the better response to the treatment with bronchodilator and corticosteroid. The identification of metabolic alterations provides new insights into different HRCT phenotypes and therapeutic assessment of COPD.

[Effects of acupoint injection of autoblood on expression of pulmonary transcription factor GATA 3 and T-bet proteins and genes in asthma rats].

OBJECTIVE: To observe the effect of autoblood acupoint-injection (ABAI) on expression levels of pulmonary transacting T-cell-specific transcription factor GATA 3 (involving Th 2 cytokine expression), Th 1-specific T-box transcription factor T-box expressed in T-cells (T-bet) proteins and genes in asthmatic rats so as to explore its mechanisms underlying asthma relief. METHODS: Forty-eight male SD rats were randomized into normal control (n = 8), model (n = 10), saline acupoint-injection (SAI, n = 10), ABAI (n = 10), and Dexamethasone (DXM, n = 10) groups. Asthma model was established during 28 days by 10% Ovalbumin + 10% aluminium hydroxide solution injection (i. p.) and vapourized 2% Ovalbumin inhaling for 14 days. For rats of the ABAI group, 0.4 mL autoblood was injected into the bilateral "Feishu" (BL 13) or "Shenshu" (BL 23) alternately, once every other day for six times. For rats of the DXM group, 50% DXM solution (0.5 mg/kg, i. p.) was given from the 17th day on after starting the modeling, once every other day for 11 days. Pulmonary GATA 3 and T-bet protein expression was detected by immunohistochemistry, and GATA 3 mRNA and T-bet mRNA expression detected by real time-PCR. RESULTS: In comparison with the normal group, pulmonary GATA 3 protein and mRNA expression levels in the model group were up-regulated significantly (P < 0.01), while T-bet mRNA expression in the model group was down-regulated obviously (P < 0.01). Compared to the model group, GATA 3 protein and mRNA expression levels were down-regulated significantly in both ABAI and DXM groups (P < 0.01), while T-bet protein expression in ABAI group and T-bet mRNA expression in both ABAI and DXM groups were up-regulated significantly (P < 0.01, P < 0.05). No significant differences were found between model and SAI groups, and between ABAI and DXM groups in GATA 3 protein expression levels; and between ABAI and DXM groups in GATA 3 mRNA expression levels; between normal and model groups, and between SAI and ABAI groups in T-bet protein expression levels; between model and SAI groups and between ABAI and DXM groups in T-bet mRNA expression levels (P > 0.05). The ratio of GATA 3 mRNA/T-bet mRNA expression was significantly higher in the model group than in the normal group (P < 0.01), while obviously lower in the SAI, ABAI and DXM groups than in the model group (P < 0.05, P < 0.01). Additionally, the ratios of GATA 3 mRNA/T-bet mRNA in ABAI and DXM groups were comparable (P > 0.05). CONCLUSION: Autoblood acupoint injection is comparable to DXM intraperitoneal injection in down-regulating asthma-induced increase of pulmonary GATA 3 protein and mRNA expression as well as ratio of GATA 3 mRNA/T-bet mRNA, and in up-regulating asthma-induced decrease of T-bet mRNA expression in asthma rats, which may contribute to their effects in relieving asthma.

[Acupoint sticking therapy for treatment of bronchial asthma: a multicenter controlled randomized clinical trial].

OBJECTIVE: To observe the effect of acupoint sticking on clinical symptoms and life quality in patients with bronchial asthma. METHODS: Multicenter randomized double-blind clinical trial was done, one hundred and eighty-eight cases were divided into a medication acupoint sticking group (125 cases) and a placebo group (63 cases). Dazhui (GV 14), Feishu (BL 13), Tiantu (CV 22), etc. were selected in both groups. The medication cakes were made of grinding pepper, brassica alba seeds, asarum, etc. into fine powder mixed with ginger oil and ginger juice, applied on acupoints in the acupoint sticking group. While another compound cakes made of powder of red rice, black rice, maize mixed with small amount of ginger juice, were used in the placebo group. Asthma Quality of Life Questionnaire(AQLQ), symptom scores during the day and night, scores of self effect, and the value of lung function were observed. RESULTS: The value of daily behavior and environmental factors of AQLQ, total scores of AQLQ, daytime symptoms and scores of self effect in the medication acupoint sticking group, were significantly improved compared to those of placebo group (all P<0.05). The lung function of forced expiratory volume in one second (FEV1) and the percentage of forced expiratory volume in one second in predicted value (FEV1/FVC) had no significant diffrence between two groups (both P>0.05). CONCLUSION: The acupoint sticking therapy can significantly improve clinical symptoms of patients with bronchial asthma, and can improve life quality of the patients.

Changes of dopamine transporter function in striatum during acute morphine addiction and its abstinence in rhesus monkey.

BACKGROUND: Although dopamine transporter (DAT) is essential for addiction, the effect of additive drugs on DAT function is still controversial, especially for opiates. We investigated the functional changes of dopamine transporter in striatum of rhesus monkeys during acute morphine injection and its abstinence. METHODS: Four rhesus monkeys, 6 to 9 years old, two male and two female, were examined for 12 days. Single photon emission computed tomography (SPECT) was performed with (99)T(cm)-TRODAT-1 as the radiopharmaceutical dopamine transporter agent during different stages of acute morphine injection and its abstinence. The ratios of SPECT signal between striatum and cerebellum (ST/CB) were calculated. RESULTS: The ST/CB ratio declined significantly on the first day of morphine injection and continued declining with more morphine injections. After abstinence, the ratio increased with time, but was still significantly lower on the 5th day of abstinence than the normal level. CONCLUSIONS: In rhesus monkey, acute morphine injection has both rapid and lasting effects on DAT by downregulating its function. The decline was partially reversible following morphine abstinence. The results suggest that striatum is one effective target of morphine and that the DAT function in striatum is one indicator for morphine addiction.

Continuous representation of human portraits and natural scenery in human ventral temporal cortex: evidence from functional magnetic resonance imaging.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has become a powerful tool for tracking human brain activity in vivo. This technique is mainly based on blood oxygenation level dependence (BOLD) contrast. In the present study, we employed this newly developed technique to characterize the neural representations of human portraits and natural sceneries in the human brain. METHODS: Nine subjects were scanned with a 1.5 T magnetic resonance imaging (MRI) scanner using gradient-recalled echo and echo-planar imaging (GRE-EPI) pulse sequence while they were visually presented with 3 types of white-black photographs: natural scenery, human portraits, and scrambled nonsense pictures. Multiple linear regression was used to identify brain regions responding preferentially to each type of stimulus and common regions for both human portraits and natural scenery. The relative contributions of each type of stimulus to activation in these regions were examined using linear combinations of a general linear test. RESULTS: Multiple linear regression analysis revealed two distinct but adjacent regions in both sides of the ventral temporal cortex. The medial region preferentially responded to natural scenery, whereas the lateral one preferentially responded to the human portraits. The general linear test further revealed a distribution gradient such that a change from portraits to scenes shifted areas of activation from lateral to medial. CONCLUSIONS: The boundary between portrait-associated and scenery-associated areas is not as clear as previously demonstrated. The representations of portraits and scenes in ventral temporal cortex appear to be continuous and overlap.