Ulnar bone tuberculosis in children: Case report and literature review.

RATIONALE: Tuberculosis of the long tubular bones in children's extremities is infrequent, particularly in the ulna. Early diagnosis poses significant challenges. This report presents a case involving a 2-year-old child with tuberculosis of the ulnar bone, accompanied by a comprehensive review of pertinent literature. The purpose of this study is to share diagnostic and therapeutic experiences and provide potentially valuable insights. PATIENT CONCERNS: In this case, the patient exhibited complete destruction and expansion of the ulnar bone, resulting in a forearm size considerably greater than normal. Concerns were raised about the irreversible deformation of the ulna, the potential for a malignant bone tumor, and its impact on forearm function, potentially endangering the patient's life. DIAGNOSES: The diagnosis was confirmed as tuberculosis of the ulnar bone. INTERVENTIONS: The patient underwent surgery to remove the affected ulnar tissue and received anti-tuberculosis medication. OUTCOMES: Subsequent to treatment, the destruction and expansion of the ulnar bone resolved, with the return of normal ulnar morphology and bone structure. LESSONS: Even in the absence of typical symptoms like fever, weight loss, and loss of appetite, extensive destruction and expansion of a long tubular bone should prompt vigilant consideration of bone tuberculosis.

Gene polymorphisms affect postoperative imatinib plasma levels and edema in adults with gastrointestinal stromal tumor.

Aim: To assess the role of genetic polymorphisms in postoperative imatinib concentrations and edema in patients with gastrointestinal stromal tumor. Methods: The relationships between genetic polymorphisms, imatinib concentrations and edema were explored. Results: Carriers of the rs683369 G-allele and rs2231142 T-allele had significantly higher imatinib concentrations. Grade ≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted odds ratio of 2.85, two T-alleles in rs1867351 with an adjusted odds ratio of 3.42 and two A-alleles in rs11636419 with an adjusted odds ratio of 3.15. Conclusion: rs683369 and rs2231142 affect the metabolism of imatinib; rs2072454, rs1867351 and rs11636419 are related to grade ≥2 periorbital edemas.

Comparison of modified U-shaped and inverted L-shaped medial capsulorrhaphy in hallux valgus surgery: a prospective, randomized controlled trial of 75 patients.

PURPOSE: The purpose of this study was to report a modified U-shaped medial capsulorrhaphy and compare its clinical and radiological differences with an inverted L-shaped capsulorrhaphy in hallux valgus (HV) surgery. METHODS: A prospective study of 78 patients was performed between January 2018 and October 2021. All patients underwent chevron osteotomy and soft tissue procedures for HV, and the patients were randomly separated into 2 groups according to the medial capsule closing techniques: a modified U-shaped capsulorrhaphy (group U) and an L-shaped capsulorrhaphy (group L). All patients were followed for at least a year. The preoperative and follow-up data were collected for each patient and included patient demographics, weight-bearing radiographs of the foot, the active range of motion (ROM) of the first metatarsophalangeal (MTP) joint and the American Orthopedic Foot and Ankle Society (AOFAS) forefoot score. Mann-Whitney U test was used for the comparison of the postoperative measures between the groups. RESULTS: In total, 75 patients with 80 affected feet met the inclusion criteria, with 38 patients (41 feet) in group U and 37 patients (39 feet) in group L. One year after surgery, the mean hallux valgus angle (HVA), intermetatarsal angle (IMA), and AOFAS score in group U improved from 29.5 to 7.1, from 13.4 to 7.1, and from 53.4 to 85.5, respectively. The mean HVA, IMA, and AOFAS score in group L improved from 31.2 to 9.6, from 13.5 to 7.9, and from 52.3 to 86.6, respectively. Comparing the 1-year postoperative measures between the 2 groups, a significant difference was found in HVA (P = 0.02), but not found in IMA and AOFAS score (P = 0.25 and P = 0.24, respectively). The mean ROM of the first MTP joint was 66.3 degrees preoperatively and 53.3 degrees at the 1-year follow-up in group U, while 63.3 and 47.5 in group L. The degrees of ROM after 1 year in group U were better than those in group L (P = 0.04). CONCLUSION: Compared to the inverted L-shaped capsulorrhaphy, the modified U-shaped capsulorrhaphy provided a better ROM of the first MTP joint; at 1 year following surgery, the modified U-shaped capsulorrhaphy maintained the normal HVA better.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Purpose: Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis.

PURPOSE: Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST. METHODS: Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202. RESULTS: A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017). CONCLUSIONS: Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.

Epifriedelanol enhances adriamycin-induced cytotoxicity towards K562/ADM cells by down regulating of P-gp and MRP2.

1. Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Epifriedelanol (Epi) is the effective compounds from the Root Bark of Ulmus davidiana. This study aims to investigate the effect of Epi on MDR and its potential mechanism in the adriamycin (Adr)-resistant K562/ADM cells.2. The effect of Epi on MDR, P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) were investigated in the adriamycin (Adr)-resistant K562/ADM cells. In addition, the alterations of nuclear receptor pregnane X receptor (PXR) and constitutive androstane receptor (CAR) mRNA expression levels in K562/ADM cells after Epi treatment were also examined.3. Epi significantly enhanced Adr-induced cytotoxicity towards K562/ADM cells. Combination of Epi and Adr can significantly reduce the 50% inhibitory concentration (IC50) of K562/ADM cells to Adr. The reversal fold was 1.83 and 3.64 after treated with Epi at 10 and 20 µM, respectively. The intracellular accumulation of Adr was significant increased after exposure to Epi at 5-20 µM compared with the control group. Furthermore, Epi treatment significantly decreased the mRNA and protein expression of P-gp and MRP2 in K562/ADM cells.4. The present study demonstrated that Epi could enhance Adr-induced cytotoxicity towards K562/ADM cells accompanied by the down-regulation of P-gp and MRP2.

[Microvesicles derived from LPS-induced microglia aggravate the injury of tight junction in rat brain microvascular endothelial cells under oxygen-glucose deprivation].

Objective To study the effect of the administration of the circulating microvesicles (MV) obtained from lipopolysaccharide (LPS)-stimulated microglia supernatant into rat brain endothelial cells (RBECs) on the injury of tight junction in RBECs under the condition of oxygen-glucose deprivation (OGD) as well as the underlying mechanism. Methods The circulating MV was isolated from the supernatant of microglia stimulated with LPS 1 mg/L for 24 hours and subjected to morphological identification. The expression of miR-27a in MV was detected by real-time PCR. RBECs were randomly divided into control group, MV-RBECs control group, OGD 6-hour group and OGD-MV group. The expressions of occludin and claudin-5 were detected by immunofluorescence staining in the four groups. Western blot analysis was used to investigate the expressions of occludin, claudin-5, Toll-like receptor 4 (TLR4), NF-κBp65 and p38 proteins in RBECs, and ELISA was applied to detect the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) in RBECs. Results The shape of MV was approximately circular double membrane vesicles, with an average diameter of 150 nm, in accordance with the morphological characteristics of MV. Under LPS stimulation, the level of miR-27a in the circulating MV was abnormally elevated. Compared with the control group, RBECs were not obviously influenced by the incubation of MV; under OGD condition, tight junction of RBECs was damaged with the decreasing expressions of occluding and claudin-5. The degree of injury was further damaged after the treatment with MV. Fluorescence intensity of occludin and claudin-5 were further reduced. Meanwhile, Western blot analysis showed the levels of occludin and claudin-5 proteins decreased in the OGD group after MV treatment, which was consistent with immunofluorescence staining. Compared with the control group, the expression of TLR4 protein and the phosphorylation of NF-κBp65 and p38 proteins increased in OGD group; after MV treatment, the level of TLR4 protein and the phosphorylation of NF-κBp65 and p38 proteins further increased, and the release of IL-1ß and TNF-α increased as well. Conclusion Treatment with the circulating MV containing miR-27a obtained from LPS-stimulated microglia supernatant damages the tight junction of RBECs under the OGD condition. The mechanism may be related to up-regulation TLR4 and phosphorylation of NF-κBp65 and p38.

UGT1A1 Gene Polymorphism Predicts Irinotecan-Induced Severe Neutropenia and Diarrhea in Chinese Cancer Patients.

BACKGROUND: Irinotecan was widely used in colon cancer and lung cancer, etc., and adverse reactions occur some times. The primary aim of this research is to investigate the association between UGT1A1 gene polymorphisms and irinotecan-related adverse effect in Chinese Han population with a novel kind of gene chip technology. METHODS: UGT1A1*6/*28 gene polymorphisms were detected by PCR and gene chip as well as sequencing. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia and effect on response rate and progression-free survival were analyzed. RESULTS: A total of 106 patients receiving irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. According to our results, no significant differences of severe diarrhea were found in patients with UGT1A1*6 genotypes (p = 0.608). However, the incidence of severe diarrhea in patients with TA7/7 genotype (66.7%, 4/6) was significantly higher than that in patients with TA6/7 (31.5%, 6/19) or TA6/6 (1.28%, 1/78) genotypes (p < 0.001). The incidence of severe hematologic toxicity in patients with AA (100%, 2/2) was significantly higher than that in patients with GA (33.3%, 7/21) or GG genotype (7.23%, 6/83) (p = 0.011). CONCLUSIONS: In terms of irinotecan-based regimens in cancers, UGT1A1*6 plays a more vital role in hematologic toxicity (p = 0.011) whereas UGT1A1*28 get more involved in diarrhea (p < 0.001).

[Regulation of P-glycoprotein gene expression by PKC/NF-κB-PXR signaling pathway].

P-glycoprotein (P-gp), an ATP binding cassette protein, plays a major role in efflux transport of drugs and xenobiotics due to its abundant expression on several barriers. This study aimed to investigate the potential role of PKC/NF-κB-PXR signaling pathway in modulation of P-gp gene expression in human colon adenocarcinoma LS174T. The effect of PMA on MDR1 luciferase activity was investigated by PXR-MDR1 dual luciferase reporter gene assay. Real-time qPCR assay and Western blot analysis were used to study the gene expression of P-gp and NF-κB, respectively. Compared to the vehicle-treated group, PMA statistically decreased P-gp luciferase activity, mRNA expression and protein expression. Moreover, PMA treatment yielded a significant and dose-dependent increase in RelA/p65 translocation to nucleus. Meanwhile, a remarkable increase of the pho-IκBα status was observed in LS174T cells after treatment with PMA (1-100 nmol·L(-1)). In addition, knockdown of PKCα, NF-κB or PXR can significantly attenuate PMA-induced P-gp suppression. These results suggested that PKC/NF-κB-PXR signaling pathway might play crucial roles in modulation of P-gp gene expression.

Zinc improves learning and memory abilities of fetal growth restriction rats and promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 axis activity.

Fetal growth restriction (FGR) is a well-known risk factor for cognitive dysfunction, especially for learning and memory abilities. However, knowledge about prevention and treatment methods of learning and memory abilities of fetal are limit. Here, Morris water maze and passive avoidance tests showed zinc supplementation could protect the impairment of the learning and memory abilities caused by FGR. As accumulating evidence suggested that insufficiency of placental trophoblast cell invasion was closely related to FGR fetal neurodevelopmental dysplasia, we further explored the relationship between zinc supplementation during pregnancy and placental trophoblast. Microarray identified 346 differently expressed genes in placental tissues with and without zinc supplementation, and GO and KEGG analyses showed these differently expressed genes were highly enriched in cell invasion and migration and STAT3 pathway. Protein-protein interaction(PPI) analysis found that STAT3 interacted with matrix metalloproteinase-2/9 (MMP-2/9). In vivo, western blot results authenticated that the expression levels of phospho-STAT3, STAT3, MMP-2 and MMP-9 were up-regulated in placental tissues after zinc treatment. To validate whether zinc could promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 activity. In vitro, Transwell assay was performed, and we observed that abilities of invasion and migration were obviously increased in zinc treated trophoblast cells. And phospho-STAT3, STAT3, MMP-2 and MMP-9 expression levels were correspondingly increased in zinc treated trophoblast cells, which were dose-dependent. Moreover, gain-of-function and loss-of-function of STAT3 confirmed that zinc promotes cell invasion and migration via regulating STAT3 mediated up-regulation of MMP-2/9 activity. We propose that activation of MMP-2/9 mediated by STAT3 may contribute to invasion and migration of trophoblast cells, which improved neurodevelopmental impairment of FGR rats probably via contributing to placental development. Our findings are the first to show a possible mechanism of reversing neurodevelopmental impairment of FGR rats by zinc supplementation, holding promise for the development of novel therapeutic modalities for learning and memory abilities impairment caused by FGR.

Mulberroside A suppresses PXR-mediated transactivation and gene expression of P-gp in LS174T cells.

Mulberroside A (Mul A) is the main bioactive constituents of Sangbaipi, which is officially listed in the Chinese Pharmacopoeia. The pregnane X receptor (PXR) has been recognized as the critical mediator of human P-glycoprotein (P-gp) gene transactivation. In this study, the effect of Mul A on PXR-mediated transactivation and gene expression of P-gp was investigated. It was found that Mul A significantly suppressed PXR-mediated P-gp luciferase activity induced by rifampicin (Rif). Furthermore, Rif induced an elevation of P-gp expression and transport activity, which was apparently suppressed by Mul A. However, Mul A did not suppress the P-gp luciferase activity, P-gp expression, and function in the absence of Rif. These findings suggest that Mul A suppresses PXR-mediated transactivation and P-gp expression induced by Rif. This should be taken into consideration to predict any potential herb-drug interactions when Mul A or Sangbaipi are co-administered with Rif or other PXR agonist drugs.

[OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 µmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) µmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 µmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.

Hydroxysafflor yellow A exerts neuroprotective effects in cerebral ischemia reperfusion-injured mice by suppressing the innate immune TLR4-inducing pathway.

The innate immune response, which is tightly regulated by Toll-like receptor 4 (TLR4) pathway, has been shown to play a critical role in brain damage following cerebral ischemia-reperfusion injury. Hydroxysafflor yellow A (HSYA) is the active component extracted from the Flos Carthami and has been reported to decrease neurological deficit scores following ischemia-reperfusion injury. However, the precise mechanism by which it exerts these neuroprotective effects remains poorly understood. In this study, we demonstrated that the administration of HSYA could significantly down-regulate TLR4 expression in middle cerebral artery occlusion (MCAO) mice. Following the down-regulation of TLR4 by HSYA treatment, cerebral infarction and inflammatory neuronal damage was alleviated. The number of apoptotic neurons in the HSYA-treated group was significantly decreased along with the decrease in TLR4 expression in MCAO mice. Activation of the NF-κB and MAPK signaling pathways was observed at 1h following ischemia and at 24h post-reperfusion. HSYA could significantly inhibit NF-κB p-p65, ERE1/2, JNK and p38 phosphorylation, which coincided with the suppressed secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and nitric oxide (NO). Moreover, brain-derived neurotrophic factor (BDNF) was up-regulated following 1h of ischemia and continued to increase initially during reperfusion but was down-regulated at later stages. Following treatment with HSYA, BDNF was up-regulated relative to control MCAO mice at 1h post-ischemia and at 12 and 24h post-reperfusion. Our data suggest that HSYA exerts neurotrophic and anti-inflammatory functions against ischemic stroke by inhibiting TLR4 pathway-mediated signaling responses.

Lateral calcaneal artery perforator-based skin flaps for coverage of lower-posterior heel defects.

BACKGROUND: Perforator-based flaps have been explored across almost all of the lower leg except in the Achilles tendon area. This paper introduced a perforator flap sourced from this area with regard to its anatomic basis and clinical applications. METHODS: Twenty-four adult cadaver legs were dissected to investigate the perforators emerging along the lateral edge of the Achilles tendon in terms of number and location relative to the tip of the lateral malleolus, and distribution. Based on the anatomic findings, perforator flaps, based on the perforator(s) of the lateral calcaneal artery (LCA) alone or in concert with the perforator of the peroneal artery (PA), were used for reconstruction of lower-posterior heel defects in eight cases. Postoperatively, subjective assessment and Semmes-Weinstein filament test were performed to evaluate the sensibility of the sural nerve-innerved area. RESULTS: The PA ended into the anterior perforating branch and LCA at the level of 6.0 ± 1.4 cm (range 3.3-9.4 cm) above the tip of the lateral malleolus. Both PA and LCA, especially the LCA, gave rise to perforators to contribute to the integument overlying the Achilles tendon. Of eight flaps, six were based on perforator(s) of the LCA and two were on perforators of the PA and LCA. Follow-up lasted for 6-28 months (mean 13.8 months), during which total flap loss and nerve injury were not found. Functional and esthetic outcomes were good in all patients. CONCLUSION: The integument overlying the Achilles tendon gets its blood supply through the perforators of the LCA primarily and that of through the PA secondarily. The LCA perforator(s)-based and the LCA plus PA perforators-based stepladder flap is a reliable, sensate flap, and should be thought of as a valuable procedure of choice for coverage of lower-posterior heel defects in selected patients.

Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro.

OBJECTIVE: To evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro. METHODS: Firstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells. RESULTS: As a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. CONCLUSION: Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.

Reactive oxygen species contribute to TRAIL receptors upregulation; the mechanism for PH II-7 augmenting TRAIL induced apoptosis in leukemia cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells and is verified to be effective in various cancers. However, a variety of cancer cells are found to be resistant to TRAIL and the mechanisms are largely unknown. Moreover, multidrug resistance to traditional chemotherapeutic agents still remains a tough problem in clinical practice. Fortunately, our previous work proved the ability of PH II-7 in overcoming MDR phenotype through reactive oxygen species production in K562 and its MDR counterpart K562/A02 cells. Additionally, we further explored its potential in augmenting TRAIL induced apoptosis in cancer cells with various tissue origins. Our results showed PH II-7 up-regulated DR4/DR5 expression and augment TRAIL cytotoxicity through reactive oxygen species production, which provide a solid foundation for TRAIL in combination with PH II-7 in future clinical application.

PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR- counterpart K562/A02 through producing reactive oxygen species.

Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which was designed and synthesized by our laboratory. Our preliminary work indicated its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effects in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells with the detailed mechanism remained to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was also induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results may provide a detailed biochemical basis for further clinical application of PHII-7.

Chemical constituents of Caesalpinia decapetala (Roth) Alston.

The current study targets the chemical constituents of Caesalpinia decapetala (Roth) Alston and investigates the bioactivities of the isolated compounds. Fourteen known compounds were isolated using column chromatography, and structural identification was performed by physical and spectral analyses. The biological activities of the compounds were also evaluated by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2,2-diphenlyl-1-picrylhydrazyl (DPPH) assays. Emodin (6), baicalein (9), and apigenin (12) displayed antitumor activities against the MGC-803 cell line, while quercetin (2), rutin (5), baicalein (9), and epicatechin (13) showed stronger DPPH scavenging activities compared with ascorbic acid. Andrographolide (1), quercetin (2), bergenin (4), rutin (5), emodin (6), betulin (7), baicalein (9), polydatin (10), salicin (11), and apigenin (12), were obtained from C. decapetala (Roth) Alston for the first time.