Incidence and Outcomes of Brucella Endocarditis in a High-Prevalence Area: A Single-Center Study.

OBJECTIVE: To analyze the clinical characteristics of Brucella endocarditis (BE) and observe the factors related to death to provide guidance for clinical treatment. METHODS: This study examined all patients with BE admitted to The First People's Hospital of Kashi Prefecture between January 2017 and November 2023. Clinical characteristics and follow-up outcomes were collected for analysis. RESULTS: This study revealed 774 cases of brucellosis and 14 cases of BE, with an overall incidence rate of 1.88%. Most of the patients were male (71.43%) and lived in areas where brucellosis is common. Patients ranged in age from 26 to 68 years. Common symptoms reported among patients included chest tightness and fatigue, and a significant portion also presented with congestive heart failure. Most patients exhibited normal white blood cell counts (WBC) but had elevated levels of C-reactive protein (CRP). Transthoracic ultrasound (TTE) revealed cardiac valve vegetation in all patients, along with positive blood cultures. Six patients (42.86%) completed heart surgery, and ten (71.43%) completed anti-infection treatment. Six patients died, five of whom did not undergo surgery. The other patient with Marfan syndrome died after surgery. Sex, WBC count, neutrophil (NEUT) and total bilirubin (TBIL) were significant factors associated with regression in BE patients (P < 0.05) according to univariate analysis. CONCLUSIONS: Patients with BE in Kashi have a severe clinical presentation at diagnosis, but early detection with improved cardiac ultrasound and aggressive treatment can improve the prognosis.

Sijunzi decoction enhances sensitivity of colon cancer cells to NK cell destruction by modulating P53 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi Decoction (SJZD), a traditional Chinese herbal remedy, is frequently employed in the treatment of various cancers, including colon cancer. Previous research suggests that SJZD plays a pivotal role in modulating the immune system and enhancing immunity against tumors. However, the precise role of SJZD in combating colon cancer and its potential molecular functions in regulating natural killer cells remain elusive. AIMS OF THE STUDY: To elucidate the potential mechanism underlying the anticolon cancer effects of SJZD in synergy with natural killer (NK) cells through both in vivo and in vitro experiments. MATERIALS AND METHODS: In vivo experiments: A subcutaneous tumor mouse model of colon cancer and in vivo NK cell depletion experiments were conducted to observe the anticolon cancer effects of SJZD. Flow cytometry assessed immune cell depletion in mouse spleens, while immunohistochemical (IHC) staining detected the expression of apoptotic genes in tumor tissues. In vitro experiments: The mechanism by which SJZD regulates the sensitization of colon cancer cells to NK cells was investigated using real-time polymerase chain reaction (RT-PCR), western blotting (WB), and co-culture experiments with NK cells. RESULTS: Sijunzi Decoction (SJZD) significantly impeded tumor growth in mice; however, NK cell depletion markedly attenuated the tumor-suppressive effect of SJZD. Immunohistochemical (IHC) results indicated that SJZD increased the expression of P53, death receptor 4 (DR4), and death receptor 5 (DR5) in tumor tissues. In vitro experiments, 24 h SJZD-pretreated colon cancer cells showed a substantial elevation in P53, DR4, and DR5 levels, and the activity of colon cancer cells significantly diminished after co-culture with NK cells. These effects of SJZD were reversed with the addition of the P53 inhibitor pifithrin-α (PFT-α), resulting in reduced inhibition of colon cancer cells by NK cells. CONCLUSION: SJZD enhances the levels of DR4 and DR5 through the modulation of P53 expression, consequently increasing the sensitivity of colon cancer cells to NK cell-mediated killing. These findings provide a theoretical foundation for the clinical application of SJZD in patients with colon cancer. In this study, we first investigated the effect of SJZD on subcutaneous tumor growth in mice with colon cancer using in vivo assays and assessed the impact of NK cells on the anticolon cancer effect of SJZD in vivo through NK cell depletion. In vitro experiments were conducted to explore the potential mechanism of action of SJZD in NK cell-mediated anticolon cancer effects.

The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy.

Background: Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. Objective: To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. Methods: A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. Results: With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. Conclusion: PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

Comparison of the efficacy and safety of TAF, TDF, and LdT to prevent the transmission of hepatitis B in pregnant women: A retrospective study.

OBJECTIVE: To compare the efficacy and safety of telbivudine (LdT), tenofovir alafenamide fumarate (TAF), and tenofovir disoproxil fumarate (TDF) for preventing hepatitis B transmission in immune-tolerant pregnant women with HBV infection. METHODS: We conducted a retrospective cohort study involving women who had hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 2 × 105 IU/mL and initiated LdT, TDF, or TAF to prevent mother-to-child transmission (MTCT). The primary endpoint was the safety of mothers and infants. The secondary endpoints were maternal HBV DNA reduction at delivery and MTCT rate. RESULTS: A total of 96 patients were enrolled in the study (LdT group, n = 36; TDF group, n = 35; TAF group, n = 25). All infants received hepatitis B virus immunoprophylaxis. The MTCT rate was 0%([0 of 25] vs. [0 of 35] vs. [0 of 36], p > .05). No severe liver function damage occurred in any of the mothers. Babies delivered in all groups had prenatal ultrasound screening abnormalities, but abnormality rates were not statistically significant between groups. CONCLUSION: The application of TDF, TAF, or LdT to immune-tolerant HBV-infected pregnant women in middle-late pregnancy can successfully interrupt MTCT of the HBV virus. However, for all three groups of pregnant women who delivered babies with abnormal prenatal ultrasound screening, an expanded sample size may be needed for further observation.

Effects of elevation and geomorphology on cadmium, lead and chromium enrichment in paddy soil and rice: A case study in the Xiangtan basin of China.

The distributions of heavy metals in paddy fields and rice along river valleys were studied to explore the key factors affecting the accumulation of heavy metals in the upstream terraces and downstream plains. Results from 975 sampling sites showed that elevation, growing season and soil organic matter (OM) had significant effects on the content of Cd and Pb in topsoil and rice. The content of Cd (0.47-0.66 mg kg-1) and Pb (49.9-68.6 mg kg-1) in paddy fields with low elevation (30-60 m) in the downstream plains was significantly higher than the content of Cd (0.29-0.38 mg kg-1) and Pb (43.9-56.3 mg kg-1) in the upstream terraces with high altitude (60-90 m). In the double-rice production area, late rice generally produced grains with higher Cd and Pb content than early rice. Soil Cd was positively increased with the content of OM, especially in the downstream plains. When elevation was used for principal component analysis, plains with low elevation were grouped together with high content of total and soluble Cd, OM and Pb in soil, as well as high content of Cd and Pb in late rice. Altitude is one of the key factors affecting Cd content in rice. Although content of Cr (93.7-138.0 mg kg-1) was significantly higher than that of Cd and Pb in soil, content of Cr was lower than that of Cd in rice. These results indicate that paddy fields with elevation of 30-60 m in the downstream plains had high risk to produce late rice with Cd and Pb content exceeding the food safety standard 0.2 mg kg-1, which may be resulted from the driving force of runoff on soil soluble Cd and Pb from terraces to alluvial plains in river valleys.

Influence of landform, soil properties, soil Cd pollution and rainfall on the spatial variation of Cd in rice: Contribution and pathway models based on big data.

Landform, soil properties, soil cadmium (Cd) pollution and rainfall are the important factors affecting the spatial variation of rice Cd. In this study, we conducted big data mining and model analysis of 150,000 rice-soil sampling sites to examine the effects by the above four factors on the spatial variation of rice Cd in Hunan Province, China. Specifically, the variable coefficient of rice Cd in space was significantly correlated with the partition scale according to the logistic fitting. The improved random forest results suggested that elevation (DEM) and pH were the two most important factors affecting the spatial variation of rice Cd, followed by relief, soil Cd content and rainfall. Typically, variance partitioning analysis (VPA) revealed that both the soil property and the interactive effects between the soil property and Cd pollution were the principal contributors to the rice-Cd variation, with the respective contributing rates of 30.5 % and 29.0 %. Meanwhile, the partial least square-structural equation modelling (PLS-SEM) elucidated 4 main paths of specific indirect effects on rice-Cd variation. They were landform → physicochemical property → soil acidity → rice-Cd variation, landform → soil acidity → rice-Cd variation, physicochemical property → soil acidity → rice-Cd variation, and soil texture → soil acidity → rice-Cd variation. This work can provide a general guidance for scientific zoning, accurate prediction and prevention of Cd pollution in paddy fields.

Silicon facilitated the physical barrier and adsorption of cadmium of iron plaque by changing the biochemical composition to reduce cadmium absorption of rice roots.

Silicon effectively inhibits cadmium (Cd) uptake in rice, iron plaque on root surface was the primary link and first interface of Cd entering into rice root. To elucidate the mechanism of iron plaque under silicon treatment on root Cd uptake, the morphological characteristics of iron plaque, mechanisms of Cd adsorption of iron plaque and effect of iron plaque on Cd uptake by rice roots of Yuzhenxiang (YZX) and Xiangwanxian (XWX) rice varieties were studied by employing energy spectrum analysis technique, non-invasive micro-test technique, and isothermal-kinetic adsorption method. Scanning electron microscopy-X-ray energy dispersive (SEM-EDX) analysis showed that denser crystal structure of iron plaque was observed at Si treatment, silicon promoted the thickening of iron plaque and strengthened the isolation of iron plaque to Cd, which reduced the Cd content of white roots of YZX and XWX varieties by 30.2% and 20.9% respectively. However, the blocking effect of iron plaque on Cd was weakened under silicon treatment with iron plaque removed, Cd content in iron plaque of YZX and XWX cultivars was significantly decreased by 36.3% and 18.4%, Cd concentrations in white root and shoot was significantly increased, and the influxes of Cd2+ at elongation and maturation zone of root were increased in multiples. The results of adsorption test showed that the adsorption process of iron plaque was mainly a monolayer adsorption completed by boundary diffusion. The X-ray photoelectron spectroscopy (XPS) results demonstrated that silicon changed the biochemical composition of iron plaque and increased the density of the carbon-oxygen bound groups on iron plaque, which is the most likely reasons for the higher affinity of Cd adsorption ability of iron plaque observed in the silicon treated iron plaque. This study suggested the silicon-facilitated iron plaque have played critical effects in controlling the Cd accumulation in rice roots by changing the morphology and chemical composition of iron plaque.

Influence of soil properties on cadmium accumulation in vegetables: Thresholds, prediction and pathway models based on big data.

Soil properties, such as soil pH, soil organic matter (SOM), cation exchange capacity (CEC), are the most important factors affecting cadmium (Cd) accumulation in vegetables. In this study, we conducted big data mining of 31,342 soil and vegetable samples to examine the influence of soil properties (soil pH, SOM, CEC, Zn and Mn content) on the accumulation of Cd in root, solanaceous, and leafy vegetables in Hunan Province, China. Specifically, the Cd accumulation capability was in the following order: leafy vegetables > root vegetables > solanaceous vegetables. The soil property thresholds for safety production in vegetables were determined by establishing nonlinear models between Cd bioaccumulation factor (BCF) and the individual soil property, and were 6.5 (pH), 30.0 g/kg (SOM), 13.0 cmol/kg (CEC), 100-140 mg/kg (Zn), and 300-400 mg/kg (Mn). When soil property values were higher than the thresholds, Cd accumulation in vegetables tended to be stable. Prediction models showed that pH and soil Zn were the leading factors influencing Cd accumulation in root vegetables, explaining 87% of the variance; pH, SOM, soil Zn and Mn explained 68% of the variance in solanaceous vegetables; pH and SOM were the main contributors in leafy vegetables, explaining 65% of the variance. Further, variance partitioning analysis (VPA) revealed that the interaction effect of the corresponding key soil properties contributed mostly to BCF. Meanwhile, partial least squares (PLS) path modeling was employed to analyze the path and the interactive effects of soil properties on Cd BCF. pH and SOM were found to be the biggest two players affecting BCF in PLS-models, and the most substantial interactive influence paths of soil properties on BCF were different among the three types of vegetables.

Efficacy and safety of danoprevir plus sofosbuvir in GT 1, 2, 3, or 6 chronic hepatitis C patients with or without cirrhosis in China.

ABSTRACT: All-oral direct-acting antiviral therapies are becoming the choice for hepatitis C (HCV) treatment. In this study, we aimed to evaluate the efficacy and safety of ritonavir-boosted danoprevir (DNVr) plus sofosbuvir±ribavirin on HCV genotype 1, 2, 3, or 6 in the real world in China.In this observational, prospective, multicenter cohort, we enrolled a total of 58 patients with HCV genotype 1, 2, 3, or 6 patients from July 2018 to December 2019. All patients were treated with DNVr plus sofosbuvir ± ribavirin for 12 weeks and then followed up for 12 weeks. The primary endpoint was the rate of sustained virologic response at week 12 after the end of treatment (SVR12). The secondary endpoint was virologic response rate at end-of-treatment and adverse event outcome.Of the 58 patients who were enrolled, 5.2% (n = 3) had genotype 1a; 43.1% (n = 25) had HCV genotype 1b; 17.2% (n = 10) had genotype 2a; 5.2% (n = 3) had genotype 3a; 8.6% (n = 5) had genotype 3b; and 20.7% (n = 12) had genotype 6a. The virologic response rate at end-of-treatment was 100% (58/58). The HCV-RNA results of 5 patients were absent at week 12 after treatment. Among the 53 patients, SVR12 rate achieved 100% (53/53) with DNVr plus sofosbuvir ± ribavirin treatment in patients with HCV genotype 1b, 2a, 3, and 6a. For compensated cirrhosis and noncirrhosis patients, SVR12 was 100% with DNVr plus sofosbuvir ± ribavirin treatment. No serious event was observed during the treatment and follow-up. Only 5 patients had mild adverse events.DNVr plus sofosbuvir ± ribavirin for 12 weeks provided 100% SVR12 in a broad patient population and were well tolerated, which may be a promising regimen for CHC treatment.

A nomogram for the prediction of renal outcomes among patients with idiopathic membranous nephropathy.

The early prediction of renal outcomes in patients with idiopathic membranous nephropathy (iMN) remains challenging. The present retrospective study evaluated patients with iMN confirmed by renal biopsy. An optimized Cox regression model and a nomogram were constructed for the early prediction of renal outcomes. A total of 141 patients who met the inclusion criteria were evaluated in the present study. In total 18 (12.8%) patients eventually progressed to the endpoint, 6 of whom developed end-stage renal disease, and one patient died during follow-up. The optimized model demonstrated that 24-h proteinuria [hazard ratio (HR) 1.24; 95% CI, 1.10-1.40; P-value <0.001] and chronic tubulointerstitial injury [referred to as grade 0, grade 1 (HR), 5.12; 95% CI, 1.33-19.75; P-value=0.02] or grade 2 (HR, 6.43; 95% CI, 1.35-30.59; P-value=0.02) were independent risk factors for a poor renal outcome. Patients with an estimated three-year renal survival rate (ETR) less than 0.87 had a high risk of a poor renal outcome. In addition, patients with an ETR of 0.87 to 0.98 more quickly developed a decreased estimated glomerular filtration rate after two years of follow-up. In the present study a nomogram for the early prediction of renal outcomes in patients with iMN was developed. This nonogram suggested that patients with an ETR of 0.87-0.98 should receive greater attention during follow-up.

Input and output of cadmium (Cd) for paddy soil in central south China: fluxes, mass balance, and model predictions.

It is important to provide a more comprehensive understanding of cadmium (Cd) input and output in different contamination zones. In this study, we choose 15 sampling areas in three types of contamination zones (industrial and mining, suburb, and rural) to systematically study the inventory of soil Cd input and output in Changzhutan (CZT) urban agglomerations, Hunan Province, China. The results showed that the value of total Cd input in industrial and mining (34.58 g/ha/year) was respectively about 2 and 3 times of that in suburb and in rural. Meanwhile, the total output flux in industrial and mining also presented highest value (38.67 g/ha/year) among the zones. As for the contributions, atmospheric deposition was responsible for 85-89% of the total input fluxes, which was significantly higher than those of irrigation water and fertilizer. Crop harvesting, especially straw removal, was the dominant output pathway, contributing 66-78%. Moreover, Cd annual balance illustrated that the net input fluxes under straw removal scenario were negative in all zones, and it was opposite under straw returning scenario. Further, the changes of soil Cd concentrations under straw returning and straw removal scenario were compared by a dynamic mathematical model. The modeling results presented that the soil Cd content continued to increase under straw returning in 100 years, while it was declining under straw removal scenario. This prediction indicated straw removal was an important remediation for Cd-polluted paddy soil, especially in Hunan. Nevertheless, more treatment measures need to conduct to reach the safety limits in paddy soil.

Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities.

Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel-like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary-induced renal injuries and underlying mechanisms in obesity. Through utilizing high-fat diet-fed mice and human renal biopsies, we provided the physiological roles of KLF4 in protecting against obesity-related nephropathy. Decreased levels of renal KLF4 were positively correlated with dietary-induced renal dysfunction, including increased levels of creatinine and blood urea nitrogen. Overexpression of renal KLF4 suppressed inflammatory response in palmitic acid-treated mouse endothelial cells. Furthermore, overexpressed KLF4 also attenuated dietary-induced renal functional disorders, abnormal structural remodelling and inflammation. Mechanistically, KLF4 maintained renal mitochondrial biogenesis and activities to combat obesity-induced mitochondrial dysfunction. In clinical renal biopsies and plasma, the renal Klf4 level was negatively associated with circulating levels of creatinine but positively associated with renal creatinine clearance. In conclusions, the present findings firstly supported that renal KLF4 played an important role in combating obesity-related nephropathy, and KLF4/mitochondrial function partially determined the energy homeostasis in chronic kidney diseases.

WNK3 Kinase Enhances the Sodium Chloride Cotransporter Expression via an ERK 1/2 Signaling Pathway.

BACKGROUND: WNK kinase is a serine/threonine kinase that plays an important role in normal blood pressure homeostasis. WNK3 was previously found to enhance the activity of sodium chloride cotransporter (NCC) in Xenopus oocyte. However, the mechanism through which it works remains unclear. METHODS: Using overexpression and siRNA knock-down techniques, the effects of WNK3 on NCC in both Cos-7 and mouse distal convoluted cells were analyzed by Western blot. RESULTS: We found that WNK3 significantly increased NCC protein expression in a dose-dependent manner. NCC protein expression in Cos-7 cells was markedly decreased after 2 h treatment with protease inhibitor, cycloheximide (CHX) in the NCC alone group, but was significantly decreased after 8 h treatment of CHX in the WNK3 + NCC group. WNK3 significantly increased NCC protein expression in both NCC alone and WNK3 + NCC groups regardless the overnight treatments of bafilomycin A1, a proton pump inhibitor, suggesting that WNK3-mediated increased NCC expression is not dependent on the lysosomal pathway. We further found that WNK3 group had a quicker NCC recovery than the control group using CHX pulse assay, suggesting that WNK3 increases NCC protein synthesis. WNK3 enhanced NCC protein level while reducing ERK 1/2 phosphorylation. In addition, knock-down of ERK 1/2 expression reversed WNK3-mediated increase of NCC expression. CONCLUSION: These results suggest that WNK3 enhances NCC protein expression by increasing NCC synthesis via an ERK 1/2-dependent signaling pathway.

Characterization of NtREL1, a novel root-specific gene from tobacco, and upstream promoter activity analysis in homologous and heterologous hosts.

KEY MESSAGE: A novel root-specific gene and its upstream promoter were cloned and characterized for potential application in root-specific expression of transgenes. The root is an important plant organ subjected to many biotic and abiotic stresses, such as infection by Ralstonia solanacearum. To isolate tobacco root-specific promoters for genetic applications, microarray screening was performed to identify genes highly and specifically expressed in the root. One root-specific gene encoding an extensin-like protein (NtREL1) was isolated, and its expression pattern was further characterized by both microarray analysis and reverse transcription-polymerase chain reaction. NtREL1 was highly expressed only in roots but not in any other organ. NtREL1 expression was affected by hormone treatment (salicylic acid, abscisic acid, and ethephon) as well as low temperature, drought, and R. solanacearum infection. A full-length 849 bp cDNA containing a 657-nucleotide open reading frame was cloned by Rapid Amplification of cDNA Ends. Subsequently, a fragment of 1,574 bp upstream of NtREL1 was isolated by flanking PCR and named pNtREL1. This promoter fragment contains TATA, GATA, and CAAT-boxes, the basic elements of a promoter, and six root-specific expression elements, namely OSE1, OSE2, ROOTMOTIFTAPOX1, SURECOREATSULTR11, P1BS, and WUSATAg. A construct containing the bacterial uidA reporter gene (ß-glucuronidase, GUS) driven by the pNtREL1 promoter was transformed into tobacco plants. GUS staining was only detected in the root, but not in leaves and stems. Additionally, transgenic tobacco plants containing peanut resveratrol synthase gene (AhRS) driven by the pNtREL1 promoter produced resveratrol only in the root. Thus, the pNtREL1 promoter can be used to direct root-specific expression of target genes to protect the root from stress or for biological studies.

miR200c attenuates P-gp-mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colorectal cancer.

MicroRNA-200c (miR200c) recently emerged as an important regulator of tumorigenicity and cancer metastasis; however, its role in regulating multidrug resistance (MDR) remains unknown. In the current study, we found that the expression levels of miR200c in recurrent and metastatic colorectal cancers were significantly lower, whereas the JNK2 expression was higher compared with primary tumors. We showed that in MDR colorectal cancer cells, miR200c targeted the 3' untranslated region of the JNK2 gene. Overexpression of miR200c attenuated the levels of p-JNK, p-c-Jun, P-gp, and MMP-2/-9, the downstream factors of the JNK signaling pathway, resulting in increased sensitivity to chemotherapeutic drugs, which was accompanied by heightened apoptosis and decreased cell invasion and migration. Moreover, in an orthotopic MDR colorectal cancer mouse model, we demonstrated that overexpression of miR200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from patients with locally advanced colorectal cancer with routine postsurgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR200c and JNK2, ABCB1, and MMP-9, thus predicting patient therapeutic outcomes. In summary, we found that miR200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR colorectal cancer cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ABCB1 signaling. Restoration of miR200c expression in MDR colorectal cancer may serve as a promising therapeutic approach in MDR-induced metastasis.

Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway.

BACKGROUND: Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. METHODS: We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. RESULTS: We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells. CONCLUSIONS: Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.

Zuo Jin Wan, a Traditional Chinese Herbal Formula, Reverses P-gp-Mediated MDR In Vitro and In Vivo.

Zuo Jin Wan (ZJW), a typical traditional Chinese medicine (TCM) formula, has been identified to have anticancer activity in recent studies. In this study, we determined the underlying mechanism of ZJW in the reversal effect of multidrug resistance on colorectal cancer in vitro and in vivo. Our results showed that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs in HCT116/L-OHP, SGC7901/DDP, and Bel/Fu MDR cells. Moreover, combination of chemotherapy with ZJW could reverse the drug resistance of HCT116/L-OHP cells, increase the sensitivity of HCT116/L-OHP cells to L-OHP, DDP, 5-Fu, and MMC in vitro, and inhibit the tumor growth in the colorectal MDR cancer xenograft model. ICP-MS results showed that ZJW could increase the concentration of chemotherapeutic drugs in HCT116/L-OHP cells in a dose-dependent manner. Furthermore, we showed that ZJW could reverse drug resistance of colorectal cancer cells by decreasing P-gp level in vitro and in vivo, which has been represented as one of the major mechanisms that contribute to the MDR phenotype. Our study has provided the first direct evidence that ZJW plays an important role in reversing multidrug resistance of human colorectal cancer and may be considered as a useful target for cancer therapy.