A hot and cold tumor­related prognostic signature for stage II colorectal cancer.

Globally, colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. Based on the presence of immune cell infiltration in the tumor microenvironment, CRC can be divided into immunologically 'hot' or 'cold' tumors, which in turn leads to the differential efficacy of immunotherapy. However, the immune characteristics of hot and cold CRC tumors remain largely elusive, prompting further investigation of their properties regarding the tumor microenvironment. In the present study, a predictive model was developed based on the differential expression of proteins between cold and hot CRC tumors. First, the differentially expressed proteins (DEPs) were identified using digital spatial profiling and mass spectrometry-based proteomics analysis, and the pathway features of the DEPs were analyzed using functional enrichment analysis. A novel eight-gene signature prognostic risk model was developed (IDO1, MAT1A, NPEPL1, NT5C, PTGR2, RPL29, TMEM126A and TUBB4B), which was validated using data obtained from The Cancer Genome Atlas. The results revealed that the risk score of the eight-gene signature acted as an independent prognostic indicator in patients with stage II CRC (T3-4N0M0). It was also found that a high-risk score in the eight-gene signature was associated with high immune cell infiltration in patients with CRC. Taken together, these findings revealed some of the differential immune characteristics of hot and cold CRC tumors, and an eight-gene signature prognostic risk model was developed, which may serve as an independent prognostic indicator for patients with stage II CRC (T3-4N0M0).

Effects of Compound Danshen Dripping Pills on Ventricular Remodeling and Cardiac Function after Acute Anterior Wall ST-Segment Elevation Myocardial Infarction (CODE-AAMI): Protocol for a Randomized Placebo-Controlled Trial.

BACKGROUND: Ventricular remodeling after acute anterior wall ST-segment elevation myocardial infarction (AAMI) is an important factor in occurrence of heart failure which additionally results in poor prognosis. Therefore, the treatment of ventricular remodeling needs to be further optimized. Compound Danshen Dripping Pills (CDDP), a traditional Chinese medicine, exerts a protective effect on microcirculatory disturbance caused by ischemia-reperfusion injury and attenuates ventricular remodeling after myocardial infarction. OBJECTIVE: This study is designed to evaluate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function after AAMI on a larger scale. METHODS: This study is a multi-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The total of 268 patients with AAMI after primary percutaneous coronary intervention (pPCI) will be randomly assigned 1:1 to the CDDP group (n=134) and control group (n=134) with a follow-up of 48 weeks. Both groups will be treated with standard therapy of ST-segment elevation myocardial infarction (STEMI), with the CDDP group administrating 20 tablets of CDDP before pPCI and 10 tablets 3 times daily after pPCI, and the control group treated with a placebo simultaneously. The primary endpoint is 48-week echocardiographic outcomes including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI). The secondary endpoint includes the change in N terminal pro-B-type natriuretic peptide (NT-proBNP) level, arrhythmias, and cardiovascular events (death, cardiac arrest, or cardiopulmonary resuscitation, rehospitalization due to heart failure or angina pectoris, deterioration of cardiac function, and stroke). Investigators and patients are both blinded to the allocated treatment. DISCUSSION: This prospective study will investigate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function in patients undergoing pPCI for a first AAMI. Patients in the CDDP group will be compared with those in the control group. If certified to be effective, CDDP treatment in AAMI will probably be advised on a larger scale. (Trial registration No. NCT05000411).

tRF-20-M0NK5Y93-induced MALAT1 promotes colon cancer metastasis through alternative splicing of SMC1A.

Recent studies have indicated that changes in the tumor microenvironment, such as hypoxia, result in the discrepant expression of noncoding small RNA tRNA-derived fragments (tRFs), affecting the phenotype of tumor metastasis. The biological function of tRFs in tumors has attracted increasing attention, but the mechanism by which tRFs mediate tumor metastasis has not been clarified. The direct regulatory relationship between tRFs and lncRNAs and the mechanism by which noncoding RNAs regulate alternative splicing are still unknown. In this study, the mechanism of tRF-mediated SMC1A alternative splicing and regulation of colon cancer metastasis was studied from multiple dimensions of cell, molecule, animal and clinical. Our present studies revealed that tRF-20-M0NK5Y93 inhibits colon cancer metastasis and that there is a significant correlation between the expression of tRFs, metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), and SRSF2 through complete transcriptional sequencing and bioinformatics. Mechanistic investigations indicated that tRFs could regulate the expression of MALAT-1 by binding to specific sites on MALAT-1. MALAT1, which is a long noncoding RNA (lncRNA), regulates alternative splicing of (structural maintenance of chromosomes 1A) SMC1A by interaction with SRSF2, resulting in discrepant expression of various isoforms, SMC1A001, SMC1A201, SMC1A005, and SMC1A003. Our findings revealed the interaction between different types of noncoding RNAs on alternative splicing, which is expected to be a novel potential therapeutic target.

Effects of Compound Danshen Dripping Pills on Ventricular Remodeling and Cardiac Function after Acute Anterior Wall ST-Segment Elevation Myocardial Infarction (CODE-AAMI): Protocol for a Randomized Placebo-Controlled Trial / 中国结合医学杂志

BACKGROUND@#Ventricular remodeling after acute anterior wall ST-segment elevation myocardial infarction (AAMI) is an important factor in occurrence of heart failure which additionally results in poor prognosis. Therefore, the treatment of ventricular remodeling needs to be further optimized. Compound Danshen Dripping Pills (CDDP), a traditional Chinese medicine, exerts a protective effect on microcirculatory disturbance caused by ischemia-reperfusion injury and attenuates ventricular remodeling after myocardial infarction.@*OBJECTIVE@#This study is designed to evaluate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function after AAMI on a larger scale.@*METHODS@#This study is a multi-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The total of 268 patients with AAMI after primary percutaneous coronary intervention (pPCI) will be randomly assigned 1:1 to the CDDP group (n=134) and control group (n=134) with a follow-up of 48 weeks. Both groups will be treated with standard therapy of ST-segment elevation myocardial infarction (STEMI), with the CDDP group administrating 20 tablets of CDDP before pPCI and 10 tablets 3 times daily after pPCI, and the control group treated with a placebo simultaneously. The primary endpoint is 48-week echocardiographic outcomes including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI). The secondary endpoint includes the change in N terminal pro-B-type natriuretic peptide (NT-proBNP) level, arrhythmias, and cardiovascular events (death, cardiac arrest, or cardiopulmonary resuscitation, rehospitalization due to heart failure or angina pectoris, deterioration of cardiac function, and stroke). Investigators and patients are both blinded to the allocated treatment.@*DISCUSSION@#This prospective study will investigate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function in patients undergoing pPCI for a first AAMI. Patients in the CDDP group will be compared with those in the control group. If certified to be effective, CDDP treatment in AAMI will probably be advised on a larger scale. (Trial registration No. NCT05000411).

Synthesis and evaluation of stereoisomers of methylated catechin and epigallocatechin derivatives on modulating P-glycoprotein-mediated multidrug resistance in cancers.

P-glycoprotein (P-gp; ABCB1)-mediated drug efflux causes multidrug resistance in cancer. Previous synthetic methylated epigallocatechin (EGC) possessed promising P-gp modulating activity. In order to further improve the potency, we have synthesized some novel stereoisomers of methylated epigallocatechin (EGC) and gallocatechin (GC) as well as epicatechin (EC) and catechin (C). The (2R, 3S)-trans-methylated C derivative 25 and the (2R, 3R)-cis-methylated EC derivative 31, both containing dimethyoxylation at ring B, tri-methoxylation at ring D and oxycarbonylphenylcarbamoyl linker between ring D and C3, are the most potent in reversing P-gp mediated drug resistance with EC50 ranged from 32 nM to 93 nM. They are non-toxic to fibroblast with IC50 > 100 µM. They can inhibit the P-gp mediated drug efflux and restore the intracellular drug concentration to a cytotoxic level. They do not downregulate surface P-gp protein level to enhance drug retention. They are specific for P-gp with no or low modulating activity towards MRP1- or BCRP-mediated drug resistance. In summary, methylated C 25 and EC 31 derivatives represent a new class of potent, specific and non-toxic P-gp modulator.

Biochanin A Alleviates Cerebral Ischemia/Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress-Induced Apoptosis and p38MAPK Signaling Pathway In Vivo and In Vitro.

We have previously shown that biochanin A exhibits neuroprotective properties in the context of cerebral ischemia/reperfusion (I/R) injury. The mechanistic basis for such properties, however, remains poorly understood. This study was therefore designed to explore the manner whereby biochanin A controls endoplasmic reticulum (ER) stress, apoptosis, and inflammation within fetal rat primary cortical neurons in response to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury. For the OGD/R in vitro model system, cells were evaluated after a 2 h OGD following a 24 h reoxygenation period, whereas in vivo neurological deficits were evaluated following 2 h of ischemia and 24 h of reperfusion. The expression of proteins associated with apoptosis, ER stress (ERS), and p38 MAPK phosphorylation was evaluated in these samples. Rats treated with biochanin A exhibited reduced neurological deficits relative to control rats following MCAO/R injury. Additionally, GRP78 and CHOP levels rose following I/R modeling both in vitro and in vivo, whereas biochanin A treatment was associated with reductions in CHOP levels but further increases in GRP78 levels. In addition, OGD/R or MCAO/R were associated with markedly enhanced p38 MAPK phosphorylation that was alleviated by biochanin A treatment. Similarly, OGD/R or MCAO/R injury resulted in increases in caspase-3, caspase-12, and Bax levels as well as decreases in Bcl-2 levels, whereas biochanin A treatment was sufficient to reverse these phenotypes. Together, these findings thus demonstrate that biochanin A can alleviate cerebral I/R-induced damage at least in part via suppressing apoptosis, ER stress, and p38 MAPK signaling, thereby serving as a potent neuroprotective agent.

Increased S1P induces S1PR2 internalization to blunt the sensitivity of colorectal cancer to 5-fluorouracil via promoting intracellular uracil generation.

Sphingosine-1-phosphate (S1P), the backbone of most sphingolipids, activating S1P receptors (S1PRs) and the downstream G protein signaling has been implicated in chemoresistance. In this study we investigated the role of S1PR2 internalization in 5-fluorouracil (5-FU) resistance in human colorectal cancer (CRC). Clinical data of randomly selected 60 CRC specimens showed the correlation between S1PR2 internalization and increased intracellular uracil (P < 0.001). Then we explored the regulatory mechanisms in CRC model of villin-S1PR2-/- mice and CRC cell lines. We showed that co-administration of S1P promoted S1PR2 internalization from plasma membrane (PM) to endoplasmic reticulum (ER), thus blunted 5-FU efficacy against colorectal tumors in WT mice, compared to that in S1PR2-/- mice. In HCT116 and HT-29 cells, application of S1P (10 µM) empowered S1PR2 to internalize from PM to ER, thus inducing 5-FU resistance, whereas the specific S1PR2 inhibitor JTE-013 (10 µM) effectively inhibited S1P-induced S1PR2 internalization. Using Mag-Fluo-AM-labeling [Ca2+]ER and LC-ESI-MS/MS, we revealed that internalized S1PR2 triggered elevating [Ca2+]ER levels to activate PERK-eLF2α-ATF4 signaling in HCT116 cells. The activated ATF4 upregulated RNASET2-mediated uracil generation, which impaired exogenous 5-FU uptake to blunt 5-FU therapy. Overall, this study reveals a previously unrecognized mechanism of 5-FU resistance resulted from S1PR2 internalization-upregulated uracil generation in colorectal cancer, and provides the novel insight into the significance of S1PR2 localization in predicting the benefit of CRC patients from 5-FU-based chemotherapy.

Observation on Tuina plus needling the distal acupoints along the pathway of meridians for shoulder periarthritis / 针灸推拿医学（英文版）

Objective: To observe the clinical efficacy of Tuina (Chinese therapeutic massage) plus needling the distal acupoints along the pathway of meridians for shoulder periarthritis (SP). Methods: A total of 70 patients with SP were divided into an observation group and a control group using the random number table method, with 35 cases in each group. The patients in the observation group were treated by Tuina combined with needling distal acupoints along the pathway of meridians, while those in the control group only received the same Tuina treatment as in the observation group. The visual analog scale (VAS) and shoulder joint function were scored before and after treatment, and the efficacy after treatment was evaluated. Results: After three courses of treatment, the total effective rate of the observation group was 94.3％, while the total effective rate of the control group was 80.0％, showing a statistical difference (P<0.05). After treatment, the VAS scores of the two groups were significantly lower than the baseline scores (P<0.01), and the VAS score of the observation group was lower than that of the control group (P<0.01). After treatment, the total scores of internal rotation, external rotation, back touching, ear touching and motion function in the two groups were significantly higher than those before treatment (P<0.01), and the above five scores in the observation group were significantly higher than those in the control group (P<0.01). Conclusion: Tuina combined with needling the distal acupoints along the pathway of meridians is more effective than Tuina alone in treating SP. The combined therapy can relieve the pain and improve joint function more effectively.

SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression.

Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD (p < 0.001). Then the regulatory mechanism was explored in CRC models of villin-SphK2 Tg mice, SphK2-/-mice, and human CRC cells xenografted nude mice. Assays of ChIP-Seq and luciferase reporter gene demonstrated that high SphK2 upregulated DPD through promoting the HDAC1-mediated H3K56ac, leading to the degradation of intracellular 5-FU into inactive α-fluoro-ß-alanine (FBAL). Lastly, inhibition of SphK2 by SLR080811 exhibited excellent inhibition on DPD expression and potently reversed 5-FU resistance in colorectal tumors of villin-SphK2 Tg mice. Overall, this study manifests that SphK2high conferred 5-FU resistance through upregulating tumoral DPD, which highlights the strategies of blocking SphK2 to overcome 5-FU resistance in CRC.

Novel α-Lipoic Acid/3-n-Butylphthalide Conjugate Enhances Protective Effects against Oxidative Stress and 6-OHDA Induced Neuronal Damage.

Neurodegenerative diseases are irreversible conditions that result in progressive degeneration and death of nerve cells. Although the underlying mechanisms may vary, oxidative stress is considered to be one of the major causes of neuronal loss. Importantly, there are still no comprehensive treatments to completely cure these diseases. Therefore, protecting neurons from oxidative damage may be the most effective therapeutic strategy. Here we report a neuroprotective effects of a novel hybrid compound (dlx-23), obtained by conjugating α-lipoic acid (ALA), a natural antioxidant agent, and 3-n-butylphthalide (NBP), a clinical anti-ischemic drug. Dlx-23 protected against neuronal death induced by both H2O2 induced oxidative stress in Cath.-a-differentiated (CAD) cells and 6-OHDA, a toxin model of Parkinson's disease (PD) in SH-SY5Y cells. These activities proved to be more potent than the parent compound (ALA) alone. Dlx-23 scavenged free radicals, increased glutathione levels, and prevented mitochondria damage. In addition, live imaging of primary cortical neurons demonstrated that dlx-23 protected against neuronal growth cone damage induced by H2O2. Taken together these results suggest that dlx-23 has substantial potential to be further developed into a novel neuroprotective agent against oxidative damage and toxin induced neurodegeneration.

S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer.

In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with the in vivo HCT116DPD cells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01%-75.87%. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into α-fluoro-ß-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs. SIGNIFICANCE: This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.

Rhodium-Catalyzed Asymmetric Allylic Dearomatization of ß-Naphthols: Enantioselective Control of Prochiral Nucleophiles.

A highly enantioselective rhodium-catalyzed allylic dearomatization of ß-naphthols with racemic aryl vinyl carbinol is described. In the presence of a Rh-catalyst derived from [Rh(C2H4)Cl]2 and chiral (P, olefin)-ligand with TFA as an additive, the functionalized ß-naphthalenone compounds bearing an all-carbon-substituted quaternary stereogenic center were obtained in good yields with excellent enantioselectivity. In addition, this protocol features the enantioselective control of prochiral nucleophiles and provides the first illustration of Rh-catalyzed asymmetric allylic dearomatization.

[Effects of Salvia przewalskii Maxim. on high-altitude pulmonary hypertension in rats and its mechanism].

OBJECTIVE: To investigate the interventive effects of Salvia przewalskii Maxim.(SPM)on high-altitude pulmonary hypertension(HAPH)in rats and possible mechanism. METHODS: The male SD rats were randomly divided into the control group, the hypoxia group and SPM(0.5 g/kg,1 g/kg and 2 g/kg) group. There were 14 rats in each group. The rats in control group were feed in Xining(with an altitude about 2 260 m), and the other group rats were all feed in Maduo county people's hospital(with an altitude about 4 260 m). The rats in SPM groups were treated with SPM at the doses of 0.5 g/kg,1 g/kg and 2 g/kg by gavage respectively (100 g/ml). The rats in control and the hypoxia groups were received equal volume of distilled water, once a day. After 4 weeks, the mean pulmonary artery pressure (mPAP) of rats was measured and the same part of lung tissue of each rat was collected and stored in liquid nitrogen. Then the relative mRNA expression levels of the proliferation cell nuclear antigen(PCNA), the cell cycle dependent kinase 4(CDK4), CyclinD1, RhoA, ROCK1, ROCK2 in lung tissues of each group rats were all tested by RT-PCR. RESULTS: Compared with the control group, the mPAP and the relative mRNA expression levels of PCNA, CDK4, CyclinD1, RhoA, ROCK1 and ROCK2 were increased significantly in the hypoxia group(P＜0.01). Compared with the hypoxia group, the mPAP and the relative mRNA expression levels of PCNA, CDK4, CyclinD1, RhoA, ROCK1 and ROCK2 in the lung tissues of the SPM group rats were all decreased significantly(P＜ 0.05 or P＜0.01). CONCLUSION: SPM can prevent the HAPH in rats, and the mechanisms may be related to the inhibition of the excessive proliferation of smooth muscle cells in pulmonary artery and the excessive activation of the RhoA/Rho kinase(ROCK) signaling pathway.

Observation on therapeutic effect of acupuncture at abdomen acupoints plus tuina for lumbar intervertebral disc herniation / 针灸推拿医学（英文版）

Objective:To observe the clinical efficacy of acupuncture at abdomen acupoints plus tuina for lumbar intervertebral disc herniation (LIDH).Methods:A total of 70 patients with LIDH were randomized into an observation group and a control group,with 35 cases in each group.The observation group was treated with acupuncture at abdomen acupoints plus tuina,while the control group was treated only with tuina treatment.The clinical efficacy was observed after one course of treatment.Results:The cure rate and the total effective rate of the observation group were 83.3％ and 96.7％,respectively.The cure rate and the total effective rate of the control group were 39.4％ and 78.8％,respectively.There were significant differences in the cured rate and the total effective rate between the two groups (both P＜0.05).There was no significant difference in Japanese Orthopedic Association (JOA) score between the two groups before treatment (P＞0.05).After treatment,the JOA scores of both groups increased significantly,and the intra-group differences were statistically significant (both P＜0.05);the JOA score of the observation group was significantly higher than that of the control group (P＜0.05).Conclusion:Acupuncture at abdomen acupoints plus tuina has a better therapeutic effect than tuina alone in the treatment of LIDH.

Regio- and Enantioselective Rhodium-Catalyzed Allylic Alkylation of Racemic Allylic Alcohols with 1,3-Diketones.

Highly regio- and enantioselective rhodium-catalyzed allylic alkylation of 1,3-diketones with racemic secondary allylic alcohols is reported. In the presence of a Rh-catalyst derived from the Carreira (P, olefin)-ligand and TFA as an additive, chiral branched α-allylated 1,3-diketones could be obtained in good to excellent yields, with excellent regio- and enantioselectivity ( b/ l > 19/1, 86-98% ee). The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of an atom economy. Both aryl- and aliphatic-substituted allyl alcohols are suitable substrates with excellent reaction outcomes. This reaction features mild conditions, broad substrate scope, and readily available substrates.

Structural modification of oridonin via DAST induced rearrangement.

A simple and efficient protocol was developed for the syntheses of oridonin analogues, i.e. 6,20-epoxy ent-kaurane diterpenoid analogues from oridonin via diethylaminosulfur trifluoride (DAST) promoted rearrangement, most of which exhibited superior anticancer activities compared with their precursor.

A Yellow-Emitting Homoleptic Iridium(III) Complex Constructed from a Multifunctional Spiro Ligand for Highly Efficient Phosphorescent Organic Light-Emitting Diodes.

To suppress concentration quenching and to improve charge-carrier injection/transport in the emission layer (EML) of phosphorescent organic light-emitting diodes (PhOLEDs), a facial homoleptic iridium(III) complex emitter with amorphous characteristics was designed and prepared in one step from a multifunctional spiro ligand containing spiro[fluorene-9,9'-xanthene] (SFX) unit. Single-crystal X-ray analysis of the resulting fac-Ir(SFXpy)3 complex revealed an enlarged Ir···Ir distance and negligible intermolecular π-π interactions between the spiro ligands. The emitter exhibits yellow emission and almost equal energy levels compared to the commercial phosphor iridium(III) bis(4-phenylthieno[3,2-c]pyridinato-N,C2')acetylacetonate (PO-01). Dry-processed devices using a common host, 4,4'-bis(N-carbazolyl)-1,1'-biphenyl, and the fac-Ir(SFXpy)3 emitter at a doping concentration of 15 wt % exhibited a peak performance of 46.2 cd A-1, 36.3 lm W-1, and 12.1% for the current efficiency (CE), power efficiency (PE), and external quantum efficiency (EQE), respectively. Compared to control devices using PO-01 as the dopant, the fac-Ir(SFXpy)3-based devices remained superior in the doping range between 8 and 15 wt %. The current densities went up with increasing doping concentration at the same driving voltage, while the roll-offs remain relatively low even at high doping levels. The superior performance of the new emitter-based devices was ascribed to key roles of the spiro ligand for suppressing aggregation and assisting charge-carrier injection/transport. Benefiting from the amorphous stability of the emitter, the wet-processed device also exhibited respectful CE, PE, and EQE of 32.2 cd A-1, 22.1 lm W-1, and 11.3%, respectively, while the EQE roll-off was as low as 1.7% at the luminance of 1000 cd m-2. The three-dimensional geometry and binary-conjugation features render SFX the ideal multifunctional module for suppressing concentration quenching, facilitating charge-carrier injection/transport, and improving the amorphous stability of iridium(III)-based phosphorescent emitters.

Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors.

In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC50 of 120-165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil. Mechanistic study demonstrates that compound 23 reverses P-gp mediated drug resistance by inhibiting transport activity of P-gp, thereby restoring intracellular drug accumulation. In summary, our study demonstrates that ningalin B analogue 23 is a non-cytotoxic and effective P-gp chemosensitizer that can be used in the future for reversing P-gp mediated clinical cancer drug resistance.