To explore the in vitro and in vivo synergistic effect of paclitaxel in combination with co-listin against MDREscherichia coli(E.coli)and the corresponding mechanism of synergism,we measured the MICs of PTX alone and combination of PTX+antimicrobial drugs on E.coli and Staphylococcus aureus(S.aureus)by broth microdilution method.Then,checkerboard method was used to determine the FICI of PTX+COL combination,and the antibacterial synergies of PTX and COL was further explored through analyzing the membrane permeability and efflux pump ac-tivity.The MICs results showed that the MIC values of PTX alone against E.coli(G5,E25)and S.aureus S238 were＞1 024 mg/L and 512 mg/L,respectively.Meanwhile,we found that the anti-bacterial activity of COL against E.coli could be significantly enhanced(MIC decreased by 4 to 8 times)when used in combination with PTX.The checkerboard test showed that the FICI values of PTX combined with COL for E.coli(G5,E25)were 0.31 and 0.29,respectively,indicating a synergistic antibacterial effect on these strains.The FICI values of PTX combined with COL for E.coli G21,S.aureus(S237 and S238)were 0.51,0.75 and 0.53,respectively,indicating additive effects on these strains.In the mouse abdominal infection model,the combination group could ex-tremely significantly reduce the bacterial burden of E.coli in abdominal compared to the COL or PTX alone group(P＜0.001).The analysis of membrane permeability and efflux pump activity showed that PTX combined with COL significantly increased the inner and outer membrane per-meability of E.coli(G5 and E25),and markedly inhibited the efflux pumping activity of E.coli,when compared that of PTX and COL alone(P＜0.01).The above results indicated that the com-bination of PTX and COL could exert a synergistic in vivo and in vitro antibacterial effect on COL-resistant E.coli through increasing bacterial membrane permeability and inhibiting efflux pump activity.This study provides the theoretical foundation for the development of a novel combi-nation regimen for the treatment of MDR E.coli infection.

OBJECTIVE To investigate the pharmacological efficacy and mechanism of action of Atractylenolide Ⅰ(Atr-Ⅰ)in inhibiting colorectal cancer.METHODS Among three active compounds of Atractylodes macrocephala,Atr-Ⅰ exhibited the highest anti-tumor potency by MTT assay.The optimal concentration of Atr-Ⅰ was determined.The effect of Atr-Ⅰ on LoVo cell prolifera-tion was assessed via a clonogenic assay,while its impact on apoptosis and cell cycle progression was evaluated using flow cytometry.The influence of Atr-Ⅰ on the migration and invasion of LoVo cell line was examined through wound healing and Transwell migration assays.Western blot analysis was performed to explore the effects and mechanisms of Atr-Ⅰ on proteins associated with mi-gration,proliferation,and epithelial-mesenchymal transition(EMT)in LoVo cells.The CT26 mouse subcutaneous tumor model was established,and histopathological analysis was conducted using hematoxylin-eosin(HE)staining.Western blot was also used to assess the effects of Atr-Ⅰ on EMT-related proteins in mouse tissues to elucidate underlying mechanisms.RESULTS Atr-Ⅰ significantly reduced colorectal cancer cell viability,with statistically significant differences between treatment and control groups(P<0.05,P<0.01).Atr-Ⅰ induced apoptosis in LoVo cells,with the treatment group showing significant differences compared to the control(P<0.05,P<0.01).Cell cycle analysis revealed that Atr-Ⅰ exerted anti-tumor effects by inducing G2/M phase arrest,with increased G2 phase cell numbers in the LoVo treatment group compared to the control(P<0.05).Wound healing and Transwell migration assays confirmed that Atr-Ⅰ significantly inhibited tumor cell migration and invasion(P<0.05,P<0.01).Western blot analysis demonstra-ted that Atr-Ⅰ specifically suppressed the expression of c-Myc and Bcl-2(P<0.05),as well as cell cycle-related proteins CDK1,Cyclin B1,and Cyclin D1(P<0.05),and angiogenesis-related proteins VEGF and MMP9(P<0.05).Additionally,Atr-Ⅰ down-regulated EMT-related protein N-cadherin and upregulated E-cadherin expression(P<0.05).It also reduced the expression of p-AKT and p-S6K1(P<0.05).CONCLUSION Atr-Ⅰ exhibits potent anti-tumor effects against colorectal cancer,potentially through modulation of the AKT/S6K1 signaling pathway.

To explore the in vitro and in vivo synergistic effect of paclitaxel in combination with co-listin against MDREscherichia coli(E.coli)and the corresponding mechanism of synergism,we measured the MICs of PTX alone and combination of PTX+antimicrobial drugs on E.coli and Staphylococcus aureus(S.aureus)by broth microdilution method.Then,checkerboard method was used to determine the FICI of PTX+COL combination,and the antibacterial synergies of PTX and COL was further explored through analyzing the membrane permeability and efflux pump ac-tivity.The MICs results showed that the MIC values of PTX alone against E.coli(G5,E25)and S.aureus S238 were＞1 024 mg/L and 512 mg/L,respectively.Meanwhile,we found that the anti-bacterial activity of COL against E.coli could be significantly enhanced(MIC decreased by 4 to 8 times)when used in combination with PTX.The checkerboard test showed that the FICI values of PTX combined with COL for E.coli(G5,E25)were 0.31 and 0.29,respectively,indicating a synergistic antibacterial effect on these strains.The FICI values of PTX combined with COL for E.coli G21,S.aureus(S237 and S238)were 0.51,0.75 and 0.53,respectively,indicating additive effects on these strains.In the mouse abdominal infection model,the combination group could ex-tremely significantly reduce the bacterial burden of E.coli in abdominal compared to the COL or PTX alone group(P＜0.001).The analysis of membrane permeability and efflux pump activity showed that PTX combined with COL significantly increased the inner and outer membrane per-meability of E.coli(G5 and E25),and markedly inhibited the efflux pumping activity of E.coli,when compared that of PTX and COL alone(P＜0.01).The above results indicated that the com-bination of PTX and COL could exert a synergistic in vivo and in vitro antibacterial effect on COL-resistant E.coli through increasing bacterial membrane permeability and inhibiting efflux pump activity.This study provides the theoretical foundation for the development of a novel combi-nation regimen for the treatment of MDR E.coli infection.

OBJECTIVE To investigate the pharmacological efficacy and mechanism of action of Atractylenolide Ⅰ(Atr-Ⅰ)in inhibiting colorectal cancer.METHODS Among three active compounds of Atractylodes macrocephala,Atr-Ⅰ exhibited the highest anti-tumor potency by MTT assay.The optimal concentration of Atr-Ⅰ was determined.The effect of Atr-Ⅰ on LoVo cell prolifera-tion was assessed via a clonogenic assay,while its impact on apoptosis and cell cycle progression was evaluated using flow cytometry.The influence of Atr-Ⅰ on the migration and invasion of LoVo cell line was examined through wound healing and Transwell migration assays.Western blot analysis was performed to explore the effects and mechanisms of Atr-Ⅰ on proteins associated with mi-gration,proliferation,and epithelial-mesenchymal transition(EMT)in LoVo cells.The CT26 mouse subcutaneous tumor model was established,and histopathological analysis was conducted using hematoxylin-eosin(HE)staining.Western blot was also used to assess the effects of Atr-Ⅰ on EMT-related proteins in mouse tissues to elucidate underlying mechanisms.RESULTS Atr-Ⅰ significantly reduced colorectal cancer cell viability,with statistically significant differences between treatment and control groups(P<0.05,P<0.01).Atr-Ⅰ induced apoptosis in LoVo cells,with the treatment group showing significant differences compared to the control(P<0.05,P<0.01).Cell cycle analysis revealed that Atr-Ⅰ exerted anti-tumor effects by inducing G2/M phase arrest,with increased G2 phase cell numbers in the LoVo treatment group compared to the control(P<0.05).Wound healing and Transwell migration assays confirmed that Atr-Ⅰ significantly inhibited tumor cell migration and invasion(P<0.05,P<0.01).Western blot analysis demonstra-ted that Atr-Ⅰ specifically suppressed the expression of c-Myc and Bcl-2(P<0.05),as well as cell cycle-related proteins CDK1,Cyclin B1,and Cyclin D1(P<0.05),and angiogenesis-related proteins VEGF and MMP9(P<0.05).Additionally,Atr-Ⅰ down-regulated EMT-related protein N-cadherin and upregulated E-cadherin expression(P<0.05).It also reduced the expression of p-AKT and p-S6K1(P<0.05).CONCLUSION Atr-Ⅰ exhibits potent anti-tumor effects against colorectal cancer,potentially through modulation of the AKT/S6K1 signaling pathway.

Sepsis-induced liver injury (SILI) is an important cause of septicemia deaths. BaWeiBaiDuSan (BWBDS) was extracted from a formula of Panax ginseng C. A. Meyer, Lilium brownie F. E. Brown ex Miellez var. viridulum Baker, Polygonatum sibiricum Delar. ex Redoute, Lonicera japonica Thunb., Hippophae rhamnoides Linn., Amygdalus Communis Vas, Platycodon grandiflorus (Jacq.) A. DC., and Cortex Phelloderdri. Herein, we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota. BWBDS protected mice against SILI, which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity. BWBDS selectively promoted the growth of Lactobacillus johnsonii (L. johnsonii) in cecal ligation and puncture treated mice. Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects. Notably, L. johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity, increasing interleukin-10⁺ M2 macrophage production and enhancing intestinal integrity. Furthermore, heat inactivation L. johnsonii (HI-L. johnsonii) treatment promoted macrophage anti-inflammatory activity and alleviated SILI. Our findings revealed BWBDS and gut microbiota L. johnsonii as novel prebiotic and probiotic that may be used to treat SILI. The potential underlying mechanism was at least in part, via L. johnsonii-dependent immune regulation and interleukin-10⁺ M2 macrophage production.

[This corrects the article DOI: 10.1016/j.apsb.2022.10.016.].

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (IκBα) and then activate nuclear factor kappa-B (NF-κB). Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKKβ is constitutively activated in healthy donors and healthy Ikkβ ^C46A (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation. These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ ^WT littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ ^C46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in Ikkβ ^C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.

Objective:To investigate the effects of respiratory mechanics-guided sedation strategy on diaphragm function in chronic obstructive pulmonary disease (COPD) patients treated with mechanical ventilation (MV).Methods:A prospective study was conducted. Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) received invasive MV who were admitted to the Affiliated Huxi Hospital of Jining Medical University from May 2020 to May 2021 were enrolled. The patients were divided into observational group and control group by random number table method. All patients were intubated for MV, and received bronchodilators, glucocorticoid, anti-infectives, expectorant, nutritional support, analgesia and sedation. The sedatives were dexmedetomidine combined with propofol, and the analgesics were sufentanil in both groups. Respiratory mechanics monitoring was performed every 6 hours in the observational group, and the depth of sedation was adjusted according to the parameters of respiratory mechanics: when airway resistance (Raw) > 20 cmH 2O·L -1·s -1, deep sedation was given to maintain Richmond agitation-sedation scale (RASS) ≤ -3; when the Raw was 10-20 cmH 2O·L -1·s -1, the initial depth of sedation maintained to reach the RASS score of -2-0; when Raw < 10 cmH 2O·L -1·s -1, withdrawn the sedation, or given light sedation, and maintained the RASS score of -2-0. While the control group received light sedation. The patients' diaphragmatic excursions (DE) was measured by bedside ultrasound, tidal volume (VT) and respiratory rate (RR) were recorded, and the diaphragmatic rapid shallow breathing index (D-RSBI, D-RSBI = RR/DE) and diaphragmatic excursion efficiency (DEE, DEE = VT/DE) were calculated. The differences in DE, D-RSBI, and DEE before and 3 days and 5 days of treatment between the two groups were compared. The difference in the RASS score within 3 days of sedation between the two groups was compared. The differences in the duration of MV and 28-day mortality between the two groups were compared. Results:A total of 96 patients were selected. Six patients were excluded due to delirium or the duration of MV shorter than 3 days. Finally, 90 patients were enrolled, with 46 in the observational group, and 44 in the control group. There were no statistically significant differences in DE, D-RSBI or DEE before treatment between the two groups. After treatment, D-RSBI in both groups was gradually decreased, and DEE was gradually increased with time. The D-RSBI at 3 days and 5 days of treatment in the observational group were significantly lower than those in the control group (times·min -1·mm -1: 1.73±0.48 vs. 1.96±0.35 at 3 days, 1.45±0.64 vs. 1.72±0.40 at 5 days, both P < 0.05), and DEE were significantly higher than those in the control group (mL/mm: 19.7±4.3 vs. 17.1±3.9 at 3 days, 25.8±5.6 vs. 22.9±5.4 at 5 days, both P < 0.05). There was no significant difference in DE at all time points between the two groups. The RASS scores within 2 hours of sedation in the observational group were significantly lower than those in the control group (1 day: -3.78±0.92 vs. -2.34±0.68, 2 days: -2.87±1.04 vs. -2.43±0.79, both P < 0.05), while no statistical difference at 3 days was found between the two groups. The duration of MV in the observational group was significantly shorter than that in the control group (days: 5.78±2.01 vs. 6.84±2.27, P < 0.05). One patient died in each of the control group and the observational group, and there was no significant difference in the 28-day mortality between the two groups (2.3% vs. 2.2%, P > 0.05). Conclusion:For AECOPD patients undergoing MV, respiratory mechanics-guided sedation strategy can reduce D-RSBI, increase DEE, shorten the duration of MV, and have a certain protective effect on the diaphragm.

Objective:To explore whether NSBB is suitable for the primary prevention of liver cirrhosis accompanied by CSPH with no or small esophageal varices.Methods:Relevant literatures were retrieved from Cochrane library, PubMed, EMBASE, SinoMed, CNKI and Wanfang databases until December 12, 2020. All randomized controlled trials (RCTs) on NSBB use for primary prevention of cirrhosis accompanied by CSPH with no or small esophageal varices were collected. The literature was strictly screened according to the established inclusion and exclusion criteria, odds ratio (OR), and 95% confidence interval (CI) combined effect size. The development of esophageal varices and the initial upper gastrointestinal bleeding were the primary outcome measures. Death (with a maximum average follow-up of about five years) and adverse events (adverse drug reactions, etc.) were the secondary outcome measures.Results:A total of 9 RCTs with 1396 cases were included. Meta-analysis results showed that, compared with placebo, NSBB significantly reduced the incidence of liver cirrhosis accompanied by CSPH with no or small esophageal varices to large esophageal varices progression ( OR=0.51, 95% CI: 0.29-0.89, P=0.02), and mortality (with maximum average follow-up of about five years) ( OR=0.64, 95% CI: 0.44-0.92, P=0.02); however, there was no statistically significant difference in the initial upper gastrointestinal bleeding rate between the two groups ( OR=0.82, 95% CI: 0.44-1.52, P=0.53). Adverse event incidence was greater in the NSBB than the placebo group ( OR=1.74, 95% CI: 1.27-2.37, P=0.0005). Conclusions:NSBB use cannot reduce the initial upper gastrointestinal bleeding rate or adverse event incidence in patients with liver cirrhosis accompanied by CSPH with no or small esophageal varices, but it can delay the progression of gastroesophageal varices and reduce patient mortality.

Objective:To investigate the clinical curative effect of hyperbaric oxygen (HBO) combined with ultrasound on pathological scars in early intervention.Methods:A total of 102 patients with pathologic scars admitted to the outpatient and the inpatient departments of Wuyi Traditional Chinese Medicine Hospital from June 2017 to November 2019 were randomly divided into ultrasound group, HBO group, and HBO+ ultrasound group, with 34 patients in each group. The ultrasound group only received ultrasound treatment; the HBO group only received HBO therapy; the HBO+ ultrasound group received HBO therapy combined with ultrasound treatment. Before and after treatment, Vancouver scar scale (VSS), visual analogue scale (VAS), and the patient and observer scar assessment scale (POSAS) were used to evaluate scar healing.Results:After 6 courses of treatment, the total scores of VSS, VAS, and POSAS in the three groups were significantly lower than those before treatment ( P<0.05). Compared with the ultrasound group and the HBO group after treatment, the total scores of VSS, VAS, and POSAS of the HBO+ ultrasound group were significantly lower ( P<0.05). After 6 courses of treatment, within the ultrasound group, comparing the scores of VSS, VAS, and POSAS of the patients with total body surface area (TBSA) 2.1%-5.0% with those of the patients with TBSA 1.1%-2.0% and with the patients with 0.5%-1.0%, there was no significant difference ( P>0.05). In both the HBO group and the HBO+ ultrasound group, the VSS, VAS, and POSAS scores of the patients with TBSA 2.1%-5.0% were significantly higher than those of the patients with TBSA 1.1%-2.0% and 0.5%-1.0%; and all the differences were statistically significant ( P<0.05). Conclusion:HBO combined with ultrasound treatment can achieve a significant curative effect on pathological scars in early intervention, which is worthy of clinical application.